Competing interests: Jochen Reiser has pending and issued patents on novel strategies for kidney therapeutics and stands to gain royalties from their commercialization. He is co-founder of TRISAQ (Miami, FL, USA), a biotechnology company in which he has financial interest, including stock. MA declares that he has no competing interests. Show Accepted 2016 Jan 21. Copyright : © 2016 Reiser J and Altintas MM This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. AbstractPodocytes are highly specialized cells of the kidney glomerulus that wrap around capillaries and that neighbor cells of the Bowman’s capsule. When it comes to glomerular filtration, podocytes play an active role in preventing plasma proteins from entering the urinary ultrafiltrate by providing a barrier comprising filtration slits between foot processes, which in aggregate represent a dynamic network of cellular extensions. Foot processes interdigitate with foot processes from adjacent podocytes and form a network of narrow and rather uniform gaps. The fenestrated endothelial cells retain blood cells but permit passage of small solutes and an overlying basement membrane less permeable to macromolecules, in particular to albumin. The cytoskeletal dynamics and structural plasticity of podocytes as well as the signaling between each of these distinct layers are essential for an efficient glomerular filtration and thus for proper renal function. The genetic or acquired impairment of podocytes may lead to foot process effacement (podocyte fusion or retraction), a morphological hallmark of proteinuric renal diseases. Here, we briefly discuss aspects of a contemporary view of podocytes in glomerular filtration, the patterns of structural changes in podocytes associated with common glomerular diseases, and the current state of basic and clinical research. Keywords: Podocytes, kidney glomerulus, urinary ultrafiltrate, glomerular filtration Podocytes and glomerular filtrationPodocytes (or visceral epithelial cells) are terminally differentiated cells lining the outer surface of the glomerular capillaries. As a major component of the ultrafiltration apparatus, podocytes have a complex cellular architecture consisting of cell body, major processes that extend outward from their cell body, forming interdigitated foot processes (FPs) that enwrap the glomerular capillaries . Major processes are tethered by microtubules and intermediate filaments while FPs contain actin-based cytoskeleton – . Podocyte FPs comprise a functioning slit diaphragm (SD) in between , , a meshwork of proteins actively participating in podocyte signaling – . In addition, FPs have a thick, negatively charged coat (glycocalyx) facing the urinary space ; this accounts for negative surface charges throughout the glomerular filtration barrier, which generates an electrostatic repel between the neighboring FPs and helps maintain the unique cytoarchitecture of podocytes by enhancing the physical separation . Podocytes form the glomerular filtration barrier together with the opposing monolayers of fenestrated endothelium in the vascular space and glomerular basement membrane (GBM) in between , . This three-layer filtration barrier serves as a size-selective and charge-dependent molecular sieve facilitating the filtration of cationic molecules, electrolytes, and small and midsized solutes but restricting the passage of anionic molecules and macromolecules , . It is important to bear in mind that those layers should be arranged with decreasing selectivity, with the SD being the least selective filter; otherwise, retained plasma proteins would routinely accumulate behind the filtration slits of podocytes . This elegant structure has to oppose hydrostatic pressure in the glomerular capillary, which is the natural driving force behind macromolecular filtration. If podocytes are injured, mutated, or lost, the elaborate structure of podocytes is physically altered—a process termed ‘foot process effacement’, which is found in many proteinuric kidney diseases. In some cases, once FPs are effaced (flattened down and fused), the glomerular filtration barrier is no longer intact as evidently indicated by the massive leak of proteins out of the vasculature into the urine, known as proteinuria . Proteinuria (also referred to as ‘albuminuria’ or ‘microalbuminuria’) is a clinically important sign of early renal dysfunction. In the following sections, we outline the response of podocytes to various stimuli or injury (or both) to better understand the mechanisms underlying podocyte FP effacement, proteinuria, and glomerular disease progression. Major causes of podocyte injuryPodocyte function depends on a highly ordered cellular arrangement of filtration compartments and the correct signaling within this microenvironment. Therefore, podocytes are uniquely sensitive to a variety of agents interfering with their actin cytoskeleton, their apical membrane domain (i.e., the negative surface charge), SD complex that regulates podocyte actin reorganization, and GBM structure to which podocytes adhere – . The mechanisms leading to podocytopathies at the molecular level include genetic events (genetic mutations and deletions) associated with common complex diseases , . The core structural component of podocyte FPs is a highly regulated actin cytoskeletal network, which was represented either by a dense bundle of actin filaments that extends along the length of FPs or by a relatively short and branched cortical network, which is located at the cell periphery and anchors elements of the SD. The initial response of podocytes to injury is the disruption of these structures and actin dysregulation, where actin and actin-binding proteins accumulate. In experimental models aiming to study various aspects of cell and molecular biology of podocytes, it has been demonstrated that podocytes are the major targets of various soluble and cellular products, including toxins, reactive oxygen species (ROS), complements, and antibodies, as outlined in Table 1. Table 1.Agents, molecules, and genes associated with podocyte injury and foot process effacement. Means of injuryCategoryAgent/Molecule/GeneReferencesToxicityActin reorganizationAdriamycin– Diphtheria toxin– Indoxyl sulfatePuromycin aminonucleoside, – Shigatoxin– ImmunologicActin reorganizationComplement proteins– Lipopolysaccharides– Polyinosinic-polycytidylic acidAnti-GBM antibodiesRabbit anti-mouse GBM antiserum– Rabbit anti-rat GBM antiserum, Sheep anti-rabbit GBM antiserum, Charge distortionPodocyte polarityPoly-L-lysineProtamine sulfate, – Sialidase, Signaling pathway Open in a separate window GBM, glomerular basement membrane. A commonly used experimental model to induce glomerular proteinuria is puromycin aminonucleoside (PAN) injection into rats. Upon PAN treatment, podocytes undergo significant alterations ranging from FP effacement and cytoskeletal rearrangement to diminished levels of actin cytoskeleton- and SD-associated proteins – . Abnormal distribution of SD proteins and increasing levels of tight junction proteins , , are also reported. Rats develop proteinuria after 4 or 5 days. The early phase of proteinuria is related to the secretion of hyposialylated angiopoietin-like 4 (ANGPTL4) from podocytes, which binds avidly to the GBM and is sensitive to glucocorticoids . Later stages may be mediated by direct oxidative mechanisms. Many pharmacological agents, including dexamethasone , , fluvastatin , erythropoietin analog darbepoetin , mizoribine , sialic acid , and nuclear factor kappa B (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) , have been shown to possess the ability to reverse the reorganized stress fiber and cortical actin fiber phenotype observed after PAN treatment. Similar structural and functional abnormalities are observed in a rat model of adriamycin (ADR) – . However, podocyte cytoskeleton returns to almost normal appearance by day 20 in PAN-treated rats, whereas pathological and functional changes progress and proteinuria sustains during a similar period of time in ADR-induced nephropathy. Of note, most mouse strains are not susceptible to either of these reagents except BALB/c and BALB/cJ mice, which develop severe proteinuria and progressive renal failure following ADR administration , . Recently, a nuclear DNA repair protein Prkdc (protein kinase, DNA-activated, catalytic peptide) was discovered to participate in the maintenance of the mitochondrial genome and prevent ADR-induced nephropathy . Simvastatin and thiazolidinedione also confer renoprotective phenotype in response to ADR. Other toxins, which act on podocytes and have been used experimentally, include diphtheria toxin (DT) – secreted by Corynebacterium diphtheria, which causes acute loss of podocytes in inducible diphtheria toxin receptor (iDTR) mice; uremic toxin indoxyl sulfate , which decreases the expression of podocyte differentiation and functional marker proteins; and hemolytic uremic Shiga toxin – , which mediates the release of inflammatory cytokines and vasoactive mediators while potently inhibiting protein synthesis. These models represent irreversible glomerular damage with major (20% and above in vivo) podocyte depletion , which leads to progressive renal failure. If podocyte loss is less than this threshold, then podocytes have the capacity to recover the normal structure of a healthy glomerulus. Administration of lipopolysaccharides (LPS) is an example of such a reversible model – . LPS trigger podocyte FP effacement and transient proteinuria within 24 hours, which return to baseline after 3 days . Podocytes sense LPS by Toll-like receptor 4 (TLR-4) and this pro-inflammatory response upregulates expression of the co-stimulatory molecule B7-1 and the urokinase-type plasminogen activator receptor (uPAR) . LPS also induces the cytosolic variant of cathepsin L (CatL) enzyme , indicating that CatL upregulation in podocytes is associated with the development of proteinuria in mice through a mechanism that involves the cleavage of large GTPase dynamin , synaptopodin , and CD2-associated protein (CD2AP) . In a recent study, we reported that the modification of intracellular pH by glutamine uptake was a protective mechanism of cultured mouse podocytes against cytosolic CatL activity, which was markedly elevated under the disease state . Treatment of cultured human podocytes with TLR-3 immunostimulant polyinosinic-polycytidylic acid (polyIC) induces CatL mRNA and simultaneously downregulates podocyte marker protein synaptopodin , suggesting that polyIC may follow an injury pathway similar to that of LPS. Another means of podocyte injury are subepithelial immune complexes developing as a result of circulating antibodies, which damage or activate podocytes through complement-dependent processes. A number of signaling pathways have been implicated in complement-mediated podocyte injury – , in which sublethal concentrations of complement produce a pronounced but reversible disruption of the actin cytoskeleton and associated focal contacts . Other intracellular events include endoplasmic reticulum (ER) stress, production of ROS, and proteases. Focusing on immunologically induced glomerular injury, podocytes also respond to immunologic processes particularly targeting GBM. Passive administration of heterologous sera containing cross-reacting antibodies against the GBM results in vacuolization of podocytes, focal detachment of podocytes from GBM, and immediate onset of glomerulosclerosis with crescent formation – consistent with a crosstalk between podocytes and the immune system. Distortion of glomerular charge selectivity by neutralization of the negative charges on podocytes and SDs with polycation protamine sulfate (PS) causes FPs to broaden in vivo , – and stress fibers to disintegrate in vitro in a calcium-dependent manner , . These physiological changes happen within 15 minutes following PS treatment and can be reversed by reperfusion with heparin for another 15 minutes , , . PS is also responsible for the phosphorylation of SD protein nephrin , and focal adhesion complex protein Cas . On the other hand, protamine had little or no effect on the sieving coefficient (also referred to as fractional clearance) of bovine serum albumin once added to neutralize GBM polyanions, a finding that downplays the contribution of GBM to the charge selectivity exhibited by the glomerular filtration barrier . A similar structural alteration can be induced by polycation poly-L-lysine , by removal of the sialic acid , , or by mutation in glucosamine (UDP- N-acetyl)-2-epimerase/ N-acetylmannosamine kinase ( GNE), the rate-limiting enzyme of sialic acid biosynthesis . Patients with mutations in GNE, however, develop the rare muscle disease HIBM (hereditary inclusion body myopathy) and never get kidney disease , highlighting the differences between mice and humans in this pathway in the kidney. Mutations, abnormalities, or genetic overexpression or deletion in genes encoding podocyte proteins, which are the regulators of actin cytoskeleton such as synaptopodin ( SYNPO) – , α-actinin 4 ( ACTN4) – , dynamin ( DYN) , , , aarF domain-containing kinase 4 ( ADCK4) , anillin ( ANLN) , apolipoprotein L1 ( APOL1) , RhoA-activated Rac1 GTPase-activating protein 24 ( ARHGAP24) , Rho guanine nucleotide dissociation inhibitor-α ( ARHGDIA) – , claudin-1 ( CLDN1) , chloride intracellular channel 5A ( CLIC5A) , cofilin-1 ( CFL1) , , ezrin ( EZR) , inverted formin 2 ( INF2) – , kidney ankyrin repeat-containing protein ( KANK1, KANK2, KANK4) , neuronal Wiskott-Aldrich syndrome protein (N-WASP) , class II phosphoinositide 3-kinase C2 α ( PI3KC2α) , phospholipase C ε1 ( PLCE1) , Rho family small GTP-binding protein Rac1 ( RAC1) , , rhophilin 1 ( RHPN1) , schwannomin interacting protein 1 ( SCHIP1) , and WT1-interacting protein ( WTIP) , and the ones that are associated with SD complex, including nephrin ( NPHS1) – , podocin ( NPHS2) – , CD2-associated protein ( CD2AP) , , , , Nck adaptor protein 1/2 ( NCK1, NCK2) , , , transient receptor potential cation channel 6 ( TRPC6) – , cysteine-rich motor neuron 1 ( CRIM1) , FAT atypical cadherin 1 ( FAT1) , Fyn proto-oncogene ( FYN) , , , IQ domain GTPase-activating protein 1 ( IQGAP1) , , MAGUK Inverted 2 ( MAGI-2) , myosin 1c ( MYO1C) , myosin 1e ( MYO1E) – , kin of IRRE like 1 ( NEPH1) , , and zonula occludens 1 ( ZO-1) , leads to proteinuric diseases owing to the disruption of filtration barrier and rearrangement of actin cytoskeleton. Likewise, glomerular filtration barrier is impaired if the podocyte apical membrane domain proteins maintaining the negative surface charge are lost or transferred including podocalyxin ( PC) , , protein-tyrosine phosphatase receptor o/glomerular epithelial protein 1 ( PTPRO/GLEPP1) , , cdc42 ( CDC42) , , atypical protein kinase Clambda/iota ( aPKCλ/ι) – , glucosamine uridine diphospho– N-acetylglucosamine-2-epimerase/ N-acetylmannosamine kinase ( GNE) , and Van Gogh-like (planar cell polarity) protein 2 ( VANGL2) – . Highlighting the importance of glomerular capillary wall assembly, manipulating or deleting the genes implicated in the adhesion of podocytes to GBM components such as integrin α3 ( ITGA3) , , integrin β1 ( ITGB1) , , integrin β4 ( ITGB4) , CD9 ( CD9) , CD151 ( CD151) – , type IV collagen α3/α4/α5 ( COL4A3, COL4A4, COL4A5) – , discoidin domain receptor 1 ( DDR1) , glypican 5 ( GPC5) , integrin-linked kinase ( ILK) , , , laminin β2 ( LAMB2) – , N-deacetylase/N-sulfotransferase ( NDST1) , RAP1 GTPase-activating protein ( RAP1GAP) , and talin 1 ( TLN1) causes disorganization of podocyte cytoskeletal architecture, leading to deformation in glomerular filtration. The involvement of lysosome membrane protein 2 ( SCARB2/LIMP2) in the maintenance of podocyte structure and mitochondrial proteins coenzyme Q 2 ( COQ2) , coenzyme Q 6 ( COQ6) , Mpv17 ( MPV17) , mitochondrial tRNA leucine 1 ( MTTL1) , and prohibitin ring complex subunit prohibitin-2 ( PHB2) in the redox state of podocyte is reported in genetic studies. Podocyte-specific deletion of autophagy-related 5 ( ATG5) , mammalian target of rapamycin ( MTOR) , prorenin receptor ( PRR) – , and class III phosphoinositide 3-kinase/vacuolar protein sorting 34 ( PIK3C3/VPS34) , disrupts intracellular vesicle trafficking and impairs autophagic flux. Ablation of dendrin ( DDN) improves renal survival in progressive glomerulosclerosis, whereas knockdown of survivin ( BIRC5) , a member of the inhibitor of apoptosis protein family, and Yes-associated protein ( YAP) , , a downstream target of Hippo kinases, induces podocyte apoptosis. Podocyte-specific knockout mice for vascular endothelial growth factor A ( VEGF-A) demonstrated a key role for VEGF-A signaling for the establishment and maintenance of a normal glomerular filtration barrier as well as mesangial cell survival and differentiation . A tremendous number of genetic studies were carried out to reveal the biological role of various pathways in podocytes. Regulatory genes, including β-catenin ( CTNNB1) , Notch intracellular domain 1 ( ICN1) , ILK – , negative factor ( NEF) , , Notch’s intracellular domain ( NOTCH-IC) , septin ( SEPT7) , transforming growth factor-β ( TGF-β) , tuberous sclerosis complex 1 ( TSC1) , vpr-binding protein ( VPR) , and wingless-type MMTV integration site family 1 ( WNT1) , are used as genetic switches to turn on (activate) a specific signaling pathway. There are also studies aiming to shut down (repress) a particular pathway targeting the genes such as Akt2 ( AKT2) , PINCH-1–binding ankyrin repeat domain of ILK ( ANK) , angiotensin II receptor 2 ( AT2) , CTNNB1 , , , diaphanous interacting protein ( DIP) , dickkopf WNT signaling pathway inhibitor 1 ( DKK1) , , , insulin-like growth factor-I receptor ( IGF-IR) , – , insulin receptor ( INSR) , , , NF-κB essential modulator ( NEMO) , , Notch-1 ( NOTCH1) , Notch-3 ( NOTCH3) , 3-phosphoinositide-dependent kinase-1 ( PDK1) , rapamycin-sensitive adaptor protein of mTOR ( RAPTOR) , and rapamycin-insensitive subunit of mTOR ( RICTOR) , , recombining binding protein suppressor of hairless ( RBPSUH) , SH2-domain-containing inositol polyphosphate 5-phosphatase 2 ( SHIP2) , SMAD family member 2/3 ( SMAD2, SMAD3) , and signal transducer and activator of transcription 3 ( STAT3) – . Currently, there is great interest in research into transcriptional regulation of gene expression patterns during development and differentiation of podocytes . Genetic studies and analysis of mutations in genes encoding transcription factors provide a comprehensive approach in characterizing the functional role of transcription factors. Alterations in c-Maf-inducing protein ( CMIP) , , forkhead box C2 ( FOXC2) , hypoxia-inducible factor 1 α ( HIF1A) – , Krüppel-like factor 6 ( KLF6) , LIM homeobox transcription factor 1 β ( LMX1B) – , v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB) , , nuclear factor of activated T cells (NFAT) , , paired box gene 2 ( PAX2) , podocyte-expressed 1/transcription factor 21 ( POD1/TCF21) , peroxisome proliferator-activated receptor-α ( PPARA) , Snail family zinc finger 1 ( SNAI1) , , Wilm’s tumor 1 ( WT-1) – , zinc finger E-box-binding homeobox 2 ( ZEB2) , and zinc fingers and homeoboxes 1/2/3 ( ZHX1, ZHX2, and ZHX3) were studied to enforce a particular cell fate by stimulating or suppressing the related genes. In addition to these molecules, factors, and genes implicating various means of podocyte injury, there are proteins or agents such as angiopoietin-like 3 (ANGPTL3) , B7-1 (CD80) , , cytosolic CatL – , glucose – , glutamine , insulin , integrin β3 (ITGB3) , , tumor necrosis factor-α (TNF-α) – , transient receptor potential cation channel 5/6 (TRPC5 and TRPC6) , and uPAR that are involved in the regulation of podocyte cytoskeleton. In some cases, this cytoskeletal disaggregation and the associated activation of certain pathways (including tumor suppressor protein p53 and caspases) lead to podocyte loss ( in vitro) and detachment from GBM ( in vivo). Seminal studies have shown that apoptotic stimuli are mediated by albumin – , aldosterone – , angiopoietin-like3 (ANGPTL3) , angiotensin II – , fatty acids – , glucose , , , IGF-binding protein-3 (IGFBP-3) , oxidized low-density lipoprotein (LDL) , and TGF-β1 , – . Angiotensin II and glucose might also induce podocyte autophagic processes as evidenced by the presence of the increased number of autophagosomes and autophagic genes such as LC3-2 and beclin-1. Under specific conditions, podocyte injury leads to a phenotypic conversion, where podocytes lose their epithelial features such as nephrin, P-cadherin, and ZO-1 while acquiring mesenchymal markers such as desmin, fibroblast-specific protein-1 (FSP-1), α-smooth muscle actin (α-SMA), vimentin, type I collagen, and fibronectin . This process is referred to as podocyte’s epithelial-mesenchymal transition (EMT) and is driven in some cases by endothelin-1 (ET-1) , ILK , PAN , and TGF-β1 . When infected by human immunodeficiency virus 1 (HIV-1) NEF protein , or treated by TNF-α , the podocyte gives a proliferative response marked by the loss of differentiation markers such as synaptopodin, WT-1, and GLEPP-1 and the subsequent expression of the proliferation markers such as podocyte G 1 cyclin, cyclin A, cyclin D1, and Ki-67. There is evidence that non-cytokine-soluble factors such as soluble urokinase-type plasminogen activator receptor (suPAR) cause podocyte FP effacement and proteinuria via a β3 integrin-dependent mechanism but that circulating sialylated ANGPTL4 reduces proteinuria via an endothelial β5 integrin-dependent mechanism. By contrast, podocyte-secreted hypo-sialylated ANGPTL4 causes proteinuria via interactions with the GBM . Although these complex regulatory mechanisms imply the vulnerability of podocytes, a variety of factors support podocyte differentiation and survival, including activated protein C (APC) , , bone morphogenetic protein-7 (BMP7) , , , insulin-like growth factor-II (IGF-II) , VEGF-A – , and vascular endothelial growth factor C (VEGF-C) , . Podocytes in glomerular disease pathologyAlthough the podocyte injury is not the only cause of major glomerular diseases, a stable podocyte architecture with interdigitating FPs connected by highly specialized filtration slits is essential for the maintenance and proper function of the glomerular filtration barrier. Both experimental and clinical studies have indicated a pivotal role of podocyte injury in the development and progression of glomerular diseases. A number of different conditions and health risk factors can result in glomerular disease. Nephrotic syndrome or glomerulonephritis (i.e., malfunction of glomerular filter) may be a direct result of an infection or accumulation of toxic agents in kidneys, or (podocyte- and GBM-associated) genetic defects, or may be due to a secondary insult such as a pre-existing disease occurring in the body – . This represents the conventional approach to classification of glomerular diseases, which generally meets the needs of nephrologists. The most common cause of primary glomerular disease in adults is focal segmental glomerulosclerosis (FSGS), which is defined by the scarring (sclerosis) of some but not all of the glomeruli (focal) that involves only a section of the affected glomeruli (segmental) by light microscopy of a renal biopsy specimen. In most cases, distinguishing primary (idiopathic) FSGS from the genetic form of FSGS associated with mutations in essential podocyte proteins , or secondary FSGS (linked to a variety of conditions, including viral infections, drug toxicity, or previous glomerular injury) is challenging; however, it has been proven that this heterogeneous lesion results from podocyte injury , , , . Once the integrity of podocyte FPs is lost, podocytes start to detach from underlying GBM at certain sites revealing bare areas of glomerular capillary surface. Later, these bare areas of GBM contact the Bowman’s capsule and form synechia, which represents the earliest committed FSGS lesion. This sequence of pathological events eventually leads to the development of more lesions and progression to glomerulosclerosis . Recurrence of FSGS in renal transplant recipients has given rise to the existence of permeability or circulating factor(s) acting on podocytes as the cause of primary FSGS . To date, a few plasma factors have been proposed but most of these have been found to be non-specific to FSGS serum/plasma . Recently, suPAR was found to be associated with FSGS; for example, two thirds of patients with primary FSGS exhibited high levels of suPAR and those with the highest levels had a greater chance of recurrence after transplantation . In support of this, our group found that higher suPAR levels at baseline are independently associated with faster decline in eGFR and suPAR in plasma can predict risk of developing chronic kidney disease (CKD) in healthy people up to five years before its onset . Contrary to FSGS, in which podocytes are lost in the areas of sclerosis, minimal change disease (MCD) is a reversible disorder with normal histology and does not cause podocyte depletion. Diffuse effacement of podocyte FPs (accompanied by condensation of the actin-based cytoskeleton but not associated with reduction of any key podocyte-specific protein except podocyte alpha-dystroglycan ) and loss of GBM charge are among the classic features of MCD. All of these changes, and the development of selective proteinuria, are attributed to the secretion from podocytes of a form of ANGPTL4 that lacks sialic acid residues , . An FSGS-related but morphologically distinct phenotype was observed when podocytes are infected with HIV , or induced by infections, drugs, autoimmune diseases, or organ transplants – . This phenotype is described as collapsing glomerulopathy (CG) and is characterized by extensive loss of mature podocyte markers, severe FP effacement, and focal detachment together with the collapse of the capillary loops. Importantly, podocytes re-enter the cell cycle, become capable of proliferating, and lead to the formation of crescents filling the Bowman’s space, making CG structurally distinct from other forms of FSGS , , . If left untreated, HIV-1-associated nephropathy progresses to end-stage renal disease within weeks to months, whereas the combined antiretroviral therapy, which blocks HIV-1 replication, limits podocyte hyperplasia and hypertrophy and brings podocytes back to differentiation state . Studies using animal models have demonstrated that CG can be ameliorated by using cell-cycle inhibitors or by activating transcription factors involved in podocyte differentiation ; however, full recovery from CG is scarce . The immunoglobulin A (IgA) nephropathy (IgAN), which is the most prevalent primary chronic glomerular disease worldwide , exhibits significant heterogeneity in terms of histopathologic features and clinical outcomes . Emerging data suggest that mesangial deposition of IgA1 immune complexes leads to podocyte necrosis and detachment from the GBM , with the subsequent reduction in nephrin mRNA . Obesity-related hypertension and diabetes have become epidemic health problems worldwide and major risk factors for the development of CKD . High glucose altered podocyte actin assembly in vitro , high blood glucose (hyperglycemia) induced podocyte apoptosis via the ROS-dependent pathway in obese rodents , and podocyte density and number decreased in patients with obesity-related glomerulopathy . Targeting podocytes as renal-specific therapyHuman kidney has been considered a terminally differentiated organ with minimal cellular turnover and limited capacity for repair, suggesting that kidney injuries carrying severe consequences have limited treatment options. The goal of clinical nephrologists and renal researchers should be to identify the renal protection mechanism and to develop strategies for the treatment of kidney or various renal compartments of which kidney is composed. Podocytes are probably the most likely candidate cell population to be analyzed on a molecular level since these intricate cells are the most vulnerable component of the glomerular filtration network even during early stages of injury and serve as hallmarks of a state of glomerular disease . Owing to their post-mitotic nature, podocytes have a limited capacity for cell division and do not regenerate in response to injury and loss . This leads to rapid progression of glomerular diseases unless treated. Regardless of the diverse origins of glomerular diseases, podocytes are critical determinants of outcome for all glomerular diseases, which makes podocytes a unique model for monitoring and investigating disease progression . Therefore, there has been a pronounced shift toward podocyte proteins as therapeutic targets in the last decade . Sialic acid and its precursors show efficacy in MCD and diabetic nephropathy . Mutant forms of human ANGPTL4 reduce proteinuria without causing hypertriglyceridemia in FSGS and diabetic nephropathy , . Calcineurin inhibitor cyclosporine A (CsA) stabilizes of the actin cytoskeleton and stress fibers in podocytes by blocking the calcineurin-mediated phosphorylation and CatL-facilitated degradation of synaptopodin . As mentioned earlier, suPAR, which activates integrin αvβ3 independent of uPAR, has been suggested as an FSGS factor . A specific inhibitor of integrin αvβ3, cyclo-RGDfV, ameliorates proteinuria in mouse models of nephrotic syndrome by directly targeting the upregulated integrin αvβ3 on podocytes . CD20 antibody rituximab binds to sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) and stabilizes the structure and function of podocytes treated with the sera of patients with recurrent FSGS . Abatacept blocks the interaction of B7-1 (CD80) with cytoskeletal protein talin and thereby stabilizes β1-integrin activity and prevents podocyte motility . However, these results have been subjected to criticism since uncertainties still remain, preventing us from being too optimistic about the general efficacy of abatacept – . The GTPase dynamin, which promotes endocytosis and regulates actin cytoskeleton , , is induced by small-molecule Bis-T-23 as a potential therapeutic approach . Bis-T-23 effectively promotes dynamin assembly into higher-order structures and increases actin polymerization in injured podocytes . Molecular analysis of podocytes will lead to a better understanding of disease mechanisms and therefore may enable the identification of targets for early-onset diagnostics and disease treatment. In this context, cell-based high-throughput drug screening assays quantifying the phenotypic changes in podocytes (specifically changes in morphology, F-actin cytoskeleton, focal adhesions, cell volume, and so on) offer great value for the discovery of chemotherapeutic agents. Recently, a podocyte cell-based phenotypic assay was developed and applied to identify novel podocyte-protective small molecules and establish specific drug delivery strategies . The possibilities of targeting podocytes and thereby affecting kidney disease and progression early in the course set high expectations and hopefully will provide a significant benefit to human health in the future. Notes[version 1; referees: 2 approved] Funding StatementThe author(s) declared that no grants were involved in supporting this work. NotesEditorial Note on the Review ProcessF1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version). The referees who approved this article are:
References1. Pavenstädt H, Kriz W, Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev. 2003;83(1):253–307. 10.1152/physrev.00020.2002 [PubMed] [CrossRef] [Google Scholar] 2. Andrews PM: Investigations of cytoplasmic contractile and cytoskeletal elements in the kidney glomerulus. Kidney Int. 1981;20(5):549–62. 10.1038/ki.1981.176 [PubMed] [CrossRef] [Google Scholar] 3. Kriz W, Hackenthal E, Nobiling R, et al.: A role for podocytes to counteract capillary wall distension. Kidney Int. 1994;45(2):369–76. 10.1038/ki.1994.47 [PubMed] [CrossRef] [Google Scholar] 4. Ichimura K, Kurihara H, Sakai T: Actin filament organization of foot processes in rat podocytes. J Histochem Cytochem. 2003;51(12):1589–600. 10.1177/002215540305101203 [PubMed] [CrossRef] [Google Scholar] 5. Reiser J, Kriz W, Kretzler M, et al.: The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol. 2000;11(1):1–8. [PubMed] [Google Scholar] 6. Fukasawa H, Bornheimer S, Kudlicka K, et al.: Slit diaphragms contain tight junction proteins. J Am Soc Nephrol. 2009;20(7):1491–503. 10.1681/ASN.2008101117 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 7. Huber TB, Benzing T: The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005;14(3):211–6. 10.1097/01.mnh.0000165885.85803.a8 [PubMed] [CrossRef] [Google Scholar] 8. George B, Holzman LB: Signaling from the podocyte intercellular junction to the actin cytoskeleton. Semin Nephrol. 2012;32(4):307–18. 10.1016/j.semnephrol.2012.06.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 9. Grahammer F, Schell C, Huber TB: The podocyte slit diaphragm--from a thin grey line to a complex signalling hub. Nat Rev Nephrol. 2013;9(10):587–98. 10.1038/nrneph.2013.169 [PubMed] [CrossRef] [Google Scholar] 10. Kerjaschki D, Sharkey DJ, Farquhar MG: Identification and characterization of podocalyxin--the major sialoprotein of the renal glomerular epithelial cell. J Cell Biol. 1984;98(4):1591–6. 10.1083/jcb.98.4.1591 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 11. Gelberg H, Healy L, Whiteley H, et al.: In vivo enzymatic removal of alpha 2-->6-linked sialic acid from the glomerular filtration barrier results in podocyte charge alteration and glomerular injury. Lab Invest. 1996;74(5):907–20. [PubMed] [Google Scholar] 12. Satchell SC, Braet F: Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol. 2009;296(5):F947–56. 10.1152/ajprenal.90601.2008 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 13. Kretzler M: Regulation of adhesive interaction between podocytes and glomerular basement membrane. Microsc Res Tech. 2002;57(4):247–53. 10.1002/jemt.10083 [PubMed] [CrossRef] [Google Scholar] 14. Farquhar MG: The glomerular basement membrane: not gone, just forgotten. J Clin Invest. 2006;116(8):2090–3. 10.1172/JCI29488 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 15. Tryggvason K, Wartiovaara J: How does the kidney filter plasma? Physiology (Bethesda). 2005;20(2):96–101. 10.1152/physiol.00045.2004 [PubMed] [CrossRef] [Google Scholar] 16. Menon MC, Chuang PY, He CJ: The glomerular filtration barrier: components and crosstalk. Int J Nephrol. 2012;2012: 749010. 10.1155/2012/749010 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 17. Haraldsson B, Nyström J, Deen WM: Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88(2):451–87. 10.1152/physrev.00055.2006 [PubMed] [CrossRef] [Google Scholar] 18. Mundel P, Reiser J: Proteinuria: an enzymatic disease of the podocyte? Kidney Int. 2010;77(7):571–80. 10.1038/ki.2009.424 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 19. Endlich K, Kriz W, Witzgall R: Update in podocyte biology. Curr Opin Nephrol Hypertens. 2001;10(3):331–40. [PubMed] [Google Scholar] 20. Asanuma K, Mundel P: The role of podocytes in glomerular pathobiology. Clin Exp Nephrol. 2003;7(4):255–9. 10.1007/s10157-003-0259-6 [PubMed] [CrossRef] [Google Scholar] 21. Garg P, Holzman LB: Podocytes: gaining a foothold. Exp Cell Res. 2012;318(9):955–63. 10.1016/j.yexcr.2012.02.030 [PubMed] [CrossRef] [Google Scholar] 22. Barisoni L, Schnaper HW, Kopp JB: Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy. Arch Pathol Lab Med. 2009;133(2):201–16. [PMC free article] [PubMed] [Google Scholar] 23. Bierzynska A, Soderquest K, Koziell A: Genes and podocytes - new insights into mechanisms of podocytopathy. Front Endocrinol (Lausanne). 2015;5:226. 10.3389/fendo.2014.00226 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 24. Bertram JF, Messina A, Ryan GB: In vitro effects of puromycin aminonucleoside on the ultrastructure of rat glomerular podocytes. Cell Tissue Res. 1990;260(3):555–63. 10.1007/BF00297236 [PubMed] [CrossRef] [Google Scholar] 25. Whiteside CI, Cameron R, Munk S, et al.: Podocytic cytoskeletal disaggregation and basement-membrane detachment in puromycin aminonucleoside nephrosis. Am J Pathol. 1993;142(5):1641–53. [PMC free article] [PubMed] [Google Scholar] 26. Kim YH, Goyal M, Kurnit D, et al.: Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int. 2001;60(3):957–68. 10.1046/j.1523-1755.2001.060003957.x [PubMed] [CrossRef] [Google Scholar] 27. Reiser J, Oh J, Shirato I, et al.: Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem. 2004;279(33):34827–32. 10.1074/jbc.M401973200 [PubMed] [CrossRef] [Google Scholar] 28. Marshall CB, Pippin JW, Krofft RD, et al.: Puromycin aminonucleoside induces oxidant-dependent DNA damage in podocytes in vitro and in vivo. Kidney Int. 2006;70(11):1962–73. 10.1038/sj.ki.5001965 [PubMed] [CrossRef] [Google Scholar] 29. Fukuda H, Hidaka T, Takagi-Akiba M, et al.: Podocin is translocated to cytoplasm in puromycin aminonucleoside nephrosis rats and in poor-prognosis patients with IgA nephropathy. Cell Tissue Res. 2015;360(2):391–400. 10.1007/s00441-014-2100-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 30. Kurihara H, Anderson JM, Kerjaschki D, et al.: The altered glomerular filtration slits seen in puromycin aminonucleoside nephrosis and protamine sulfate-treated rats contain the tight junction protein ZO-1. Am J Pathol. 1992;141(4):805–16. [PMC free article] [PubMed] [Google Scholar] 31. Zhao L, Yaoita E, Nameta M, et al.: Claudin-6 localized in tight junctions of rat podocytes. Am J Physiol Regul Integr Comp Physiol. 2008;294(6):R1856–62. 10.1152/ajpregu.00862.2007 [PubMed] [CrossRef] [Google Scholar] 32. Clement LC, Avila-Casado C, Macé C, et al.: Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. 2011;17(1):117–22. 10.1038/nm.2261 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 33. Wada T, Pippin JW, Marshall CB, et al.: Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2-related family proteins. J Am Soc Nephrol. 2005;16(9):2615–25. 10.1681/ASN.2005020142 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 34. Wada T, Pippin JW, Nangaku M, et al.: Dexamethasone's prosurvival benefits in podocytes require extracellular signal-regulated kinase phosphorylation. Nephron Exp Nephrol. 2008;109(1):e8–19. 10.1159/000131892 [PubMed] [CrossRef] [Google Scholar] 35. Shibata S, Nagase M, Fujita T: Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling. J Am Soc Nephrol. 2006;17(3):754–64. 10.1681/ASN.2005050571 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 36. Eto N, Wada T, Inagi R, et al.: Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression. Kidney Int. 2007;72(4):455–63. 10.1038/sj.ki.5002311 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 37. Takeuchi S, Hiromura K, Tomioka M, et al.: The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis. Nephron Exp Nephrol. 2010;116(1):e3–10. 10.1159/000314668 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 38. Pawluczyk IZ, Najafabadi MG, Brown JR, et al.: Sialic acid supplementation ameliorates puromycin aminonucleoside nephrosis in rats. Lab Invest. 2015;95(9):1019–28. 10.1038/labinvest.2015.78 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 39. Shimo T, Adachi Y, Yamanouchi S, et al.: A novel nuclear factor κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates puromycin aminonucleoside-induced nephrosis in mice. Am J Nephrol. 2013;37(4):302–9. 10.1159/000348803 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 40. Bertani T, Poggi A, Pozzoni R, et al.: Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest. 1982;46(1):16–23. [PubMed] [Google Scholar] 41. Okuda S, Oh Y, Tsuruda H, et al.: Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease. Kidney Int. 1986;29(2):502–10. 10.1038/ki.1986.28 [PubMed] [CrossRef] [Google Scholar] 42. Rossmann P, Matousovic K, Bohdanecká M: Experimental adriamycin nephropathy. Fine structure, morphometry, glomerular polyanion, and cell membrane antigens. J Pathol. 1993;169(1):99–108. 10.1002/path.1711690115 [PubMed] [CrossRef] [Google Scholar] 43. Wang Y, Wang YP, Tay YC, et al.: Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events. Kidney Int. 2000;58(4):1797–804. 10.1046/j.1523-1755.2000.00342.x [PubMed] [CrossRef] [Google Scholar] 44. Zoja C, Garcia PB, Rota C, et al.: Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in adriamycin-induced nephropathy. Am J Physiol Renal Physiol. 2012;303(9):F1370–81. 10.1152/ajprenal.00057.2012 [PubMed] [CrossRef] [Google Scholar] 45. Chen A, Wei CH, Sheu LF, et al.: Induction of proteinuria by adriamycin or bovine serum albumin in the mouse. Nephron. 1995;69(3):293–300. 10.1159/000188473 [PubMed] [CrossRef] [Google Scholar] 46. Chen A, Sheu LF, Ho YS, et al.: Experimental focal segmental glomerulosclerosis in mice. Nephron. 1998;78(4):440–52. 10.1159/000044974 [PubMed] [CrossRef] [Google Scholar] 47. Papeta N, Zheng Z, Schon EA, et al.: Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice. J Clin Invest. 2010;120(11):4055–64. 10.1172/JCI43721 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 48. Zhang W, Li Q, Wang L, et al.: Simvastatin ameliorates glomerulosclerosis in Adriamycin-induced-nephropathy rats. Pediatr Nephrol. 2008;23(12):2185–94. 10.1007/s00467-008-0933-8 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 49. Liu HF, Guo LQ, Huang YY, et al.: Thiazolidinedione attenuate proteinuria and glomerulosclerosis in Adriamycin-induced nephropathy rats via slit diaphragm protection. Nephrology (Carlton). 2010;15(1):75–83. 10.1111/j.1440-1797.2009.01146.x [PubMed] [CrossRef] [Google Scholar] 50. Wharram BL, Goyal M, Wiggins JE, et al.: Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol. 2005;16(10):2941–52. 10.1681/ASN.2005010055 [PubMed] [CrossRef] [Google Scholar] 51. Sato Y, Wharram BL, Lee SK, et al.: Urine podocyte mRNAs mark progression of renal disease. J Am Soc Nephrol. 2009;20(5):1041–52. 10.1681/ASN.2007121328 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 52. Goldwich A, Steinkasserer A, Gessner A, et al.: Impairment of podocyte function by diphtheria toxin--a new reversible proteinuria model in mice. Lab Invest. 2012;92(12):1674–85. 10.1038/labinvest.2012.133 [PubMed] [CrossRef] [Google Scholar] 53. Ichii O, Otsuka-Kanazawa S, Nakamura T, et al.: Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS One. 2014;9(9):e108448. 10.1371/journal.pone.0108448 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 54. Hughes AK, Stricklett PK, Schmid D, et al.: Cytotoxic effect of Shiga toxin-1 on human glomerular epithelial cells. Kidney Int. 2000;57(6):2350–9. 10.1046/j.1523-1755.2000.00095.x [PubMed] [CrossRef] [Google Scholar] 55. Morigi M, Buelli S, Zanchi C, et al.: Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol. 2006;169(6):1965–75. 10.2353/ajpath.2006.051331 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 56. Locatelli M, Buelli S, Pezzotta A, et al.: Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement. J Am Soc Nephrol. 2014;25(8):1786–98. 10.1681/ASN.2013050450 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 57. Reiser J, von Gersdorff G, Loos M, et al.: Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004;113(10):1390–7. 10.1172/JCI200420402 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 58. Sun Y, He L, Takemoto M, et al.: Glomerular transcriptome changes associated with lipopolysaccharide-induced proteinuria. Am J Nephrol. 2009;29(6):558–70. 10.1159/000191469 [PubMed] [CrossRef] [Google Scholar] 59. Srivastava T, Sharma M, Yew KH, et al.: LPS and PAN-induced podocyte injury in an in vitro model of minimal change disease: changes in TLR profile. J Cell Commun Signal. 2013;7(1):49–60. 10.1007/s12079-012-0184-0 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 60. Wei C, Möller CC, Altintas MM, et al.: Modification of kidney barrier function by the urokinase receptor. Nat Med. 2008;14(1):55–63. 10.1038/nm1696 [PubMed] [CrossRef] [Google Scholar] 61. Sever S, Altintas MM, Nankoe SR, et al.: Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest. 2007;117(8):2095–104. 10.1172/JCI32022 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 62. Faul C, Donnelly M, Merscher-Gomez S, et al.: The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008;14(9):931–8. 10.1038/nm.1857 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 63. Yaddanapudi S, Altintas MM, Kistler AD, et al.: CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest. 2011;121(10):3965–80. 10.1172/JCI58552 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 64. Altintas MM, Moriwaki K, Wei C, et al.: Reduction of proteinuria through podocyte alkalinization. J Biol Chem. 2014;289(25):17454–67. 10.1074/jbc.M114.568998 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 65. Shimada M, Ishimoto T, Lee PY, et al.: Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-κB-dependent pathway. Nephrol Dial Transplant. 2012;27(1):81–9. 10.1093/ndt/gfr271 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 66. Cybulsky AV, Quigg RJ, Salant DJ: Experimental membranous nephropathy redux. Am J Physiol Renal Physiol. 2005;289(4):F660–71. 10.1152/ajprenal.00437.2004 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 67. Berger SP, Daha MR: Complement in glomerular injury. Semin Immunopathol. 2007;29(4):375–84. 10.1007/s00281-007-0090-3 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 68. Noris M, Remuzzi G: Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479–92. 10.1016/j.semnephrol.2013.08.001 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 69. Takano T, Elimam H, Cybulsky AV: Complement-mediated cellular injury. Semin Nephrol. 2013;33(6):586–601. 10.1016/j.semnephrol.2013.08.009 [PubMed] [CrossRef] [Google Scholar] 70. Topham PS, Haydar SA, Kuphal R, et al.: Complement-mediated injury reversibly disrupts glomerular epithelial cell actin microfilaments and focal adhesions. Kidney Int. 1999;55(5):1763–75. 10.1046/j.1523-1755.1999.00407.x [PubMed] [CrossRef] [Google Scholar] 71. Le Hir M, Haas C, Marino M, et al.: Prevention of crescentic glomerulonephritis induced by anti-glomerular membrane antibody in tumor necrosis factor-deficient mice. Lab Invest. 1998;78(12):1625–31. [PubMed] [Google Scholar] 72. Le Hir M, Keller C, Eschmann V, et al.: Podocyte bridges between the tuft and Bowman's capsule: an early event in experimental crescentic glomerulonephritis. J Am Soc Nephrol. 2001;12(10):2060–71. [PubMed] [Google Scholar] 73. Moeller MJ, Soofi A, Hartmann I, et al.: Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J Am Soc Nephrol. 2004;15(1):61–7. 10.1097/01.ASN.0000102468.37809.C6 [PubMed] [CrossRef] [Google Scholar] 74. Wheeler J, Morley AR, Appleton DR: Anti-glomerular basement membrane (GBM) glomerulonephritis in the mouse: development of disease and cell proliferation. J Exp Pathol (Oxford). 1990;71(3):411–22. [PMC free article] [PubMed] [Google Scholar] 75. Shirato I, Hosser H, Kimura K, et al.: The development of focal segmental glomerulosclerosis in masugi nephritis is based on progressive podocyte damage. Virchows Arch. 1996;429(4–5):255–73. 10.1007/BF00198342 [PubMed] [CrossRef] [Google Scholar] 76. Shirato I, Sakai T, Kimura K, et al.: Cytoskeletal changes in podocytes associated with foot process effacement in Masugi nephritis. Am J Pathol. 1996;148(4):1283–96. [PMC free article] [PubMed] [Google Scholar] 77. Ophascharoensuk V, Pippin JW, Gordon KL, et al.: Role of intrinsic renal cells versus infiltrating cells in glomerular crescent formation. Kidney Int. 1998;54(2):416–25. 10.1046/j.1523-1755.1998.00003.x [PubMed] [CrossRef] [Google Scholar] 78. Kim YG, Alpers CE, Brugarolas J, et al.: The cyclin kinase inhibitor p21 CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis. Kidney Int. 1999;55(6):2349–61. 10.1046/j.1523-1755.1999.00504.x [PubMed] [CrossRef] [Google Scholar] 79. Seiler MW, Venkatachalam MA, Cotran RS: Glomerular epithelium: structural alterations induced by polycations. Science. 1975;189(4200):390–3. 10.1126/science.1145209 [PubMed] [CrossRef] [Google Scholar] 80. Kerjaschki D: Polycation-induced dislocation of slit diaphragms and formation of cell junctions in rat kidney glomeruli: the effects of low temperature, divalent cations, colchicine, and cytochalasin B. Lab Invest. 1978;39(5):430–40. [PubMed] [Google Scholar] 81. George B, Verma R, Soofi AA, et al.: Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest. 2012;122(2):674–92. 10.1172/JCI60070 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 82. Reiser J, Pixley FJ, Hug A, et al.: Regulation of mouse podocyte process dynamics by protein tyrosine phosphatases rapid communication. Kidney Int. 2000;57(5):2035–42. 10.1046/j.1523-1755.2000.00070.x [PubMed] [CrossRef] [Google Scholar] 83. Rüdiger F, Greger R, Nitschke R, et al.: Polycations induce calcium signaling in glomerular podocytes. Kidney Int. 1999;56(5):1700–9. 10.1046/j.1523-1755.1999.00729.x [PubMed] [CrossRef] [Google Scholar] 84. Schaldecker T, Kim S, Tarabanis C, et al.: Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. 2013;123(12):5298–309. 10.1172/JCI71165 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 85. Seiler MW, Rennke HG, Venkatachalam MA, et al.: Pathogenesis of polycation-induced alterations ("fusion") of glomerular epithelium. Lab Invest. 1977;36(1):48–61. [PubMed] [Google Scholar] 86. Verma R, Kovari I, Soofi A, et al.: Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006;116(5):1346–59. 10.1172/JCI27414 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 87. Daniels BS: Increased albumin permeability in vitro following alterations of glomerular charge is mediated by the cells of the filtration barrier. J Lab Clin Med. 1994;124(2):224–30. [PubMed] [Google Scholar] 88. Andrews PM: Glomerular epithelial alterations resulting from sialic acid surface coat removal. Kidney Int. 1979;15(4):376–85. 10.1038/ki.1979.49 [PubMed] [CrossRef] [Google Scholar] 89. Galeano B, Klootwijk R, Manoli I, et al.: Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest. 2007;117(6):1585–94. 10.1172/JCI30954 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 90. Asanuma K, Kim K, Oh J, et al.: Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner. J Clin Invest. 2005;115(5):1188–98. 10.1172/JCI200523371 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 91. Asanuma K, Yanagida-Asanuma E, Faul C, et al.: Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006;8(5):485–91. 10.1038/ncb1400 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 92. Huber TB, Kwoh C, Wu H, et al.: Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin. J Clin Invest. 2006;116(5):1337–45. 10.1172/JCI27400 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 93. Kaplan JM, Kim SH, North KN, et al.: Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24(3):251–6. 10.1038/73456 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 94. Kos CH, Le TC, Sinha S, et al.: Mice deficient in alpha-actinin-4 have severe glomerular disease. J Clin Invest. 2003;111(11):1683–90. 10.1172/JCI200317988 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 95. Michaud J, Lemieux LI, Dubé M, et al.: Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4. J Am Soc Nephrol. 2003;14(5):1200–11. 10.1097/01.ASN.0000059864.88610.5E [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 96. Michaud JL, Chaisson KM, Parks RJ, et al.: FSGS-associated alpha-actinin-4 (K256E) impairs cytoskeletal dynamics in podocytes. Kidney Int. 2006;70(6):1054–61. 10.1038/sj.ki.5001665 [PubMed] [CrossRef] [Google Scholar] 97. Gu C, Yaddanapudi S, Weins A, et al.: Direct dynamin-actin interactions regulate the actin cytoskeleton. EMBO J. 2010;29(21):3593–606. 10.1038/emboj.2010.249 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 98. Soda K, Balkin DM, Ferguson SM, et al.: Role of dynamin, synaptojanin, and endophilin in podocyte foot processes. J Clin Invest. 2012;122(12):4401–11. 10.1172/JCI65289 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 99. Ashraf S, Gee HY, Woerner S, et al.: ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ 10 biosynthesis disruption. J Clin Invest. 2013;123(12):5179–89. 10.1172/JCI69000 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 100. Gbadegesin RA, Hall G, Adeyemo A, et al.: Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS. J Am Soc Nephrol. 2014;25(9):1991–2002. 10.1681/ASN.2013090976 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 101. Lan X, Jhaveri A, Cheng K, et al.: APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability. Am J Physiol Renal Physiol. 2014;307(3):F326–36. 10.1152/ajprenal.00647.2013 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 102. Akilesh S, Suleiman H, Yu H, et al.: Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest. 2011;121(10):4127–37. 10.1172/JCI46458 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 103. Togawa A, Miyoshi J, Ishizaki H, et al.: Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha. Oncogene. 1999;18(39):5373–80. 10.1038/sj.onc.1202921 [PubMed] [CrossRef] [Google Scholar] 104. Gee HY, Saisawat P, Ashraf S, et al.: ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J Clin Invest. 2013;123(8):3243–53. 10.1172/JCI69134 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 105. Gupta IR, Baldwin C, Auguste D, et al.: ARHGDIA: a novel gene implicated in nephrotic syndrome. J Med Genet. 2013;50(5):330–8. 10.1136/jmedgenet-2012-101442 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 106. Hasegawa K, Wakino S, Simic P, et al.: Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med. 2013;19(11):1496–504. 10.1038/nm.3363 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 107. Wegner B, Al-Momany A, Kulak SC, et al.: CLIC5A, a component of the ezrin-podocalyxin complex in glomeruli, is a determinant of podocyte integrity. Am J Physiol Renal Physiol. 2010;298(6):F1492–503. 10.1152/ajprenal.00030.2010 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 108. Garg P, Verma R, Cook L, et al.: Actin-depolymerizing factor cofilin-1 is necessary in maintaining mature podocyte architecture. J Biol Chem. 2010;285(29):22676–88. 10.1074/jbc.M110.122929 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 109. Ashworth S, Teng B, Kaufeld J, et al.: Cofilin-1 inactivation leads to proteinuria--studies in zebrafish, mice and humans. PLoS One. 2010;5(9):e12626. 10.1371/journal.pone.0012626 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 110. Wasik AA, Koskelainen S, Hyvönen ME, et al.: Ezrin is down-regulated in diabetic kidney glomeruli and regulates actin reorganization and glucose uptake via GLUT1 in cultured podocytes. Am J Pathol. 2014;184(6):1727–39. 10.1016/j.ajpath.2014.03.002 [PubMed] [CrossRef] [Google Scholar] 111. Brown EJ, Schlöndorff JS, Becker DJ, et al.: Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet. 2010;42(1):72–6. 10.1038/ng.505 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 112. Boyer O, Benoit G, Gribouval O, et al.: Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol. 2011;22(2):239–45. 10.1681/ASN.2010050518 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 113. Barua M, Brown EJ, Charoonratana VT, et al.: Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int. 2013;83(2):316–22. 10.1038/ki.2012.349 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 114. Sun H, Al-Romaih KI, MacRae CA, et al.: Human Kidney Disease-causing INF2 Mutations Perturb Rho/Dia Signaling in the Glomerulus. EBioMedicine. 2014;1(2–3):107–15. 10.1016/j.ebiom.2014.11.009 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 115. Gee HY, Zhang F, Ashraf S, et al.: KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. J Clin Invest. 2015;125(6):2375–84. 10.1172/JCI79504 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 116. Schell C, Baumhakl L, Salou S, et al.: N-wasp is required for stabilization of podocyte foot processes. J Am Soc Nephrol. 2013;24(5):713–21. 10.1681/ASN.2012080844 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 117. Harris DP, Vogel P, Wims M, et al.: Requirement for class II phosphoinositide 3-kinase C2alpha in maintenance of glomerular structure and function. Mol Cell Biol. 2011;31(1):63–80. 10.1128/MCB.00468-10 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 118. Hinkes B, Wiggins RC, Gbadegesin R, et al.: Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006;38(12):1397–405. 10.1038/ng1918 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 119. Blattner SM, Hodgin JB, Nishio M, et al.: Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 2013;84(5):920–30. 10.1038/ki.2013.175 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 120. Ishizaka M, Gohda T, Takagi M, et al.: Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice. Biochem Biophys Res Commun. 2015;467(3):549–55. 10.1016/j.bbrc.2015.09.158 [PubMed] [CrossRef] [Google Scholar] 121. Lal MA, Andersson AC, Katayama K, et al.: Rhophilin-1 is a key regulator of the podocyte cytoskeleton and is essential for glomerular filtration. J Am Soc Nephrol. 2015;26(3):647–62. 10.1681/ASN.2013111195 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 122. Perisic L, Rodriguez PQ, Hultenby K, et al.: Schip1 is a novel podocyte foot process protein that mediates actin cytoskeleton rearrangements and forms a complex with Nherf2 and ezrin. PLoS One. 2015;10(3):e0122067. 10.1371/journal.pone.0122067 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 123. Kim JH, Mukherjee A, Madhavan SM, et al.: WT1-interacting protein (Wtip) regulates podocyte phenotype by cell-cell and cell-matrix contact reorganization. Am J Physiol Renal Physiol. 2012;302(1):F103–15. 10.1152/ajprenal.00419.2011 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 124. Kestilä M, Lenkkeri U, Männikkö M, et al.: Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1(4):575–82. 10.1016/S1097-2765(00)80057-X [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 125. Putaala H, Soininen R, Kilpeläinen P, et al.: The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet. 2001;10(1):1–8. 10.1093/hmg/10.1.1 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 126. Garg P, Verma R, Nihalani D, et al.: Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol. 2007;27(24):8698–712. 10.1128/MCB.00948-07 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 127. Boute N, Gribouval O, Roselli S, et al.: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet. 2000;24(4):349–54. 10.1038/74166 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 128. Huber TB, Simons M, Hartleben B, et al.: Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet. 2003;12(24):3397–405. 10.1093/hmg/ddg360 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 129. Roselli S, Heidet L, Sich M, et al.: Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol. 2004;24(2):550–60. 10.1128/MCB.24.2.550-560.2004 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 130. Shih NY, Li J, Karpitskii V, et al.: Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science. 1999;286(5438):312–5. 10.1126/science.286.5438.312 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 131. Kim JM, Wu H, Green G, et al.: CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science. 2003;300(5623):1298–300. 10.1126/science.1081068 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 132. Jones N, Blasutig IM, Eremina V, et al.: Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature. 2006;440(7085):818–23. 10.1038/nature04662 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 133. Jones N, New LA, Fortino MA, et al.: Nck proteins maintain the adult glomerular filtration barrier. J Am Soc Nephrol. 2009;20(7):1533–43. 10.1681/ASN.2009010056 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 134. Hofstra JM, Lainez S, van Kuijk WH, et al.: New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2013;28(7):1830–8. 10.1093/ndt/gfs572 [PubMed] [CrossRef] [Google Scholar] 135. Reiser J, Polu KR, Möller CC, et al.: TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37(7):739–44. 10.1038/ng1592 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 136. Winn MP, Conlon PJ, Lynn KL, et al.: A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308(5729):1801–4. 10.1126/science.1106215 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 137. Möller CC, Wei C, Altintas MM, et al.: Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. 2007;18(1):29–36. 10.1681/ASN.2006091010 [PubMed] [CrossRef] [Google Scholar] 138. Heeringa SF, Möller CC, Du J, et al.: A novel TRPC6 mutation that causes childhood FSGS. PLoS One. 2009;4(11):e7771. 10.1371/journal.pone.0007771 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 139. Schlöndorff J, Del Camino D, Carrasquillo R, et al.: TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol Cell Physiol. 2009;296(3):C558–69. 10.1152/ajpcell.00077.2008 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 140. Chiluiza D, Krishna S, Schumacher VA, et al.: Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular signal-regulated kinases 1/2 (ERK1/2). J Biol Chem. 2013;288(25):18407–20. 10.1074/jbc.M113.463059 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 141. Kistler AD, Singh G, Altintas MM, et al.: Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease. J Biol Chem. 2013;288(51):36598–609. 10.1074/jbc.M113.488122 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 142. Nyström J, Hultenby K, Ek S, et al.: CRIM1 is localized to the podocyte filtration slit diaphragm of the adult human kidney. Nephrol Dial Transplant. 2009;24(7):2038–44. 10.1093/ndt/gfn743 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 143. Ciani L, Patel A, Allen ND, et al.: Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol. 2003;23(10):3575–82. 10.1128/MCB.23.10.3575-3582.2003 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 144. Yu CC, Yen TS, Lowell CA, et al.: Lupus-like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn. Curr Biol. 2001;11(1):34–8. 10.1016/S0960-9822(00)00024-5 [PubMed] [CrossRef] [Google Scholar] 145. Verma R, Wharram B, Kovari I, et al.: Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin. J Biol Chem. 2003;278(23):20716–23. 10.1074/jbc.M301689200 [PubMed] [CrossRef] [Google Scholar] 146. Rigothier C, Auguste P, Welsh GI, et al.: IQGAP1 interacts with components of the slit diaphragm complex in podocytes and is involved in podocyte migration and permeability in vitro. PLoS One. 2012;7(5):e37695. 10.1371/journal.pone.0037695 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 147. Liu Y, Liang W, Yang Y, et al.: IQGAP1 regulates actin cytoskeleton organization in podocytes through interaction with nephrin. Cell Signal. 2015;27(4):867–77. 10.1016/j.cellsig.2015.01.015 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 148. Balbas MD, Burgess MR, Murali R, et al.: MAGI-2 scaffold protein is critical for kidney barrier function. Proc Natl Acad Sci U S A. 2014;111(41):14876–81. 10.1073/pnas.1417297111 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 149. Arif E, Wagner MC, Johnstone DB, et al.: Motor protein Myo1c is a podocyte protein that facilitates the transport of slit diaphragm protein Neph1 to the podocyte membrane. Mol Cell Biol. 2011;31(10):2134–50. 10.1128/MCB.05051-11 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 150. Krendel M, Kim SV, Willinger T, et al.: Disruption of Myosin 1e promotes podocyte injury. J Am Soc Nephrol. 2009;20(1):86–94. 10.1681/ASN.2007111172 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 151. Mele C, Iatropoulos P, Donadelli R, et al.: MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N Engl J Med. 2011;365(4):295–306. 10.1056/NEJMoa1101273 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 152. Sanna-Cherchi S, Burgess KE, Nees SN, et al.: Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome. Kidney Int. 2011;80(4):389–96. 10.1038/ki.2011.148 [PubMed] [CrossRef] [Google Scholar] 153. Chase SE, Encina CV, Stolzenburg LR, et al.: Podocyte-specific knockout of myosin 1e disrupts glomerular filtration. Am J Physiol Renal Physiol. 2012;303(7):F1099–106. 10.1152/ajprenal.00251.2012 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 154. Donoviel DB, Freed DD, Vogel H, et al.: Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol. 2001;21(14):4829–36. 10.1128/MCB.21.14.4829-4836.2001 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 155. Itoh M, Nakadate K, Horibata Y, et al.: The structural and functional organization of the podocyte filtration slits is regulated by Tjp1/ZO-1. PLoS One. 2014;9(9):e106621. 10.1371/journal.pone.0106621 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 156. Doyonnas R, Kershaw DB, Duhme C, et al.: Anuria, omphalocele, and perinatal lethality in mice lacking the CD34-related protein podocalyxin. J Exp Med. 2001;194(1):13–27. 10.1084/jem.194.1.13 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 157. Fukasawa H, Obayashi H, Schmieder S, et al.: Phosphorylation of podocalyxin (Ser415) Prevents RhoA and ezrin activation and disrupts its interaction with the actin cytoskeleton. Am J Pathol. 2011;179(5):2254–65. 10.1016/j.ajpath.2011.07.046 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 158. Wharram BL, Goyal M, Gillespie PJ, et al.: Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J Clin Invest. 2000;106(10):1281–90. 10.1172/JCI7236 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 159. Ozaltin F, Ibsirlioglu T, Taskiran EZ, et al.: Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am J Hum Genet. 2011;89(1):139–47. 10.1016/j.ajhg.2011.05.026 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 160. Scott RP, Hawley SP, Ruston J, et al.: Podocyte-specific loss of Cdc42 leads to congenital nephropathy. J Am Soc Nephrol. 2012;23(7):1149–54. 10.1681/ASN.2011121206 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 161. Hirose T, Satoh D, Kurihara H, et al.: An essential role of the universal polarity protein, aPKClambda, on the maintenance of podocyte slit diaphragms. PLoS One. 2009;4(1):e4194. 10.1371/journal.pone.0004194 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 162. Huber TB, Hartleben B, Winkelmann K, et al.: Loss of podocyte aPKClambda/iota causes polarity defects and nephrotic syndrome. J Am Soc Nephrol. 2009;20(4):798–806. 10.1681/ASN.2008080871 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 163. Satoh D, Hirose T, Harita Y, et al.: aPKCλ maintains the integrity of the glomerular slit diaphragm through trafficking of nephrin to the cell surface. J Biochem. 2014;156(2):115–28. 10.1093/jb/mvu022 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 164. Babayeva S, Zilber Y, Torban E: Planar cell polarity pathway regulates actin rearrangement, cell shape, motility, and nephrin distribution in podocytes. Am J Physiol Renal Physiol. 2011;300(2):F549–60. 10.1152/ajprenal.00566.2009 [PubMed] [CrossRef] [Google Scholar] 165. Babayeva S, Rocque B, Aoudjit L, et al.: Planar cell polarity pathway regulates nephrin endocytosis in developing podocytes. J Biol Chem. 2013;288(33):24035–48. 10.1074/jbc.M113.452904 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 166. Rocque BL, Babayeva S, Li J, et al.: Deficiency of the planar cell polarity protein Vangl2 in podocytes affects glomerular morphogenesis and increases susceptibility to injury. J Am Soc Nephrol. 2015;26(3):576–86. 10.1681/ASN.2014040340 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 167. Kreidberg JA, Donovan MJ, Goldstein SL, et al.: Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development. 1996;122(11):3537–47. [PubMed] [Google Scholar] 168. Kanasaki K, Kanda Y, Palmsten K, et al.: Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus. Dev Biol. 2008;313(2):584–93. 10.1016/j.ydbio.2007.10.047 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 169. Pozzi A, Jarad G, Moeckel GW, et al.: Beta1 integrin expression by podocytes is required to maintain glomerular structural integrity. Dev Biol. 2008;316(2):288–301. 10.1016/j.ydbio.2008.01.022 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 170. Kambham N, Tanji N, Seigle RL, et al.: Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis. 2000;36(1):190–6. 10.1053/ajkd.2000.8293 [PubMed] [CrossRef] [Google Scholar] 171. Blumenthal A, Giebel J, Warsow G, et al.: Mechanical stress enhances CD9 expression in cultured podocytes. Am J Physiol Renal Physiol. 2015;308(6):F602–13. 10.1152/ajprenal.00190.2014 [PubMed] [CrossRef] [Google Scholar] 172. Karamatic Crew V, Burton N, Kagan A, et al.: CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood. 2004;104(8):2217–23. 10.1182/blood-2004-04-1512 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 173. Sachs N, Kreft M, van den Bergh Weerman MA, et al.: Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol. 2006;175(1):33–9. 10.1083/jcb.200603073 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 174. Baleato RM, Guthrie PL, Gubler MC, et al.: Deletion of CD151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane. Am J Pathol. 2008;173(4):927–37. 10.2353/ajpath.2008.071149 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 175. Blumenthal A, Giebel J, Ummanni R, et al.: Morphology and migration of podocytes are affected by CD151 levels. Am J Physiol Renal Physiol. 2012;302(10):F1265–77. 10.1152/ajprenal.00468.2011 [PubMed] [CrossRef] [Google Scholar] 176. Hudson BG, Tryggvason K, Sundaramoorthy M, et al.: Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med. 2003;348(25):2543–56. 10.1056/NEJMra022296 [PubMed] [CrossRef] [Google Scholar] 177. Hudson BG: The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J Am Soc Nephrol. 2004;15(10):2514–27. 10.1097/01.ASN.0000141462.00630.76 [PubMed] [CrossRef] [Google Scholar] 178. Gubler MC: Inherited diseases of the glomerular basement membrane. Nat Clin Pract Nephrol. 2008;4(1):24–37. 10.1038/ncpneph0671 [PubMed] [CrossRef] [Google Scholar] 179. Gross O, Beirowski B, Harvey SJ, et al.: DDR1-deficient mice show localized subepithelial GBM thickening with focal loss of slit diaphragms and proteinuria. Kidney Int. 2004;66(1):102–11. 10.1111/j.1523-1755.2004.00712.x [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 180. Okamoto K, Tokunaga K, Doi K, et al.: Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet. 2011;43(5):459–63. 10.1038/ng.792 [PubMed] [CrossRef] [Google Scholar] 181. Dai C, Stolz DB, Bastacky SI, et al.: Essential role of integrin-linked kinase in podocyte biology: Bridging the integrin and slit diaphragm signaling. J Am Soc Nephrol. 2006;17(8):2164–75. 10.1681/ASN.2006010033 [PubMed] [CrossRef] [Google Scholar] 182. El-Aouni C, Herbach N, Blattner SM, et al.: Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. J Am Soc Nephrol. 2006;17(5):1334–44. 10.1681/ASN.2005090921 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 183. Noakes PG, Miner JH, Gautam M, et al.: The renal glomerulus of mice lacking s-laminin/laminin beta 2: nephrosis despite molecular compensation by laminin beta 1. Nat Genet. 1995;10(4):400–6. 10.1038/ng0895-400 [PubMed] [CrossRef] [Google Scholar] 184. Jarad G, Cunningham J, Shaw AS, et al.: Proteinuria precedes podocyte abnormalities in Lamb2 -/- mice, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest. 2006;116(8):2272–9. 10.1172/JCI28414 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 185. Chen YM, Kikkawa Y, Miner JH: A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion. J Am Soc Nephrol. 2011;22(5):849–58. 10.1681/ASN.2010060632 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 186. Chen YM, Zhou Y, Go G, et al.: Laminin β2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am Soc Nephrol. 2013;24(8):1223–33. 10.1681/ASN.2012121149 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 187. Sugar T, Wassenhove-McCarthy DJ, Esko JD, et al.: Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo. Kidney Int. 2014;85(2):307–18. 10.1038/ki.2013.281 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 188. Potla U, Ni J, Vadaparampil J, et al.: Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis-associated glomerular injury. J Clin Invest. 2014;124(4):1757–69. 10.1172/JCI67846 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 189. Tian X, Kim JJ, Monkley SM, et al.: Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest. 2014;124(3):1098–113. 10.1172/JCI69778 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 190. Berkovic SF, Dibbens LM, Oshlack A, et al.: Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet. 2008;82(3):673–84. 10.1016/j.ajhg.2007.12.019 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 191. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, et al.: COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol. 2007;18(10):2773–80. 10.1681/ASN.2006080833 [PubMed] [CrossRef] [Google Scholar] 192. Heeringa SF, Chernin G, Chaki M, et al.: COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011;121(5):2013–24. 10.1172/JCI45693 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 193. Casalena G, Krick S, Daehn I, et al.: Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro. Am J Physiol Renal Physiol. 2014;306(11):F1372–80. 10.1152/ajprenal.00608.2013 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 194. Löwik MM, Hol FA, Steenbergen EJ, et al.: Mitochondrial tRNA Leu(UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2005;20(2):336–41. 10.1093/ndt/gfh546 [PubMed] [CrossRef] [Google Scholar] 195. Ising C, Koehler S, Brähler S, et al.: Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol Med. 2015;7(3):275–87. 10.15252/emmm.201404916 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 196. Hartleben B, Gödel M, Meyer-Schwesinger C, et al.: Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010;120(4):1084–96. 10.1172/JCI39492 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 197. Cinà DP, Onay T, Paltoo A, et al.: Inhibition of MTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol. 2012;23(3):412–20. 10.1681/ASN.2011070690 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 198. Riediger F, Quack I, Qadri F, et al.: Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol. 2011;22(12):2193–202. 10.1681/ASN.2011020200 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 199. Oshima Y, Kinouchi K, Ichihara A, et al.: Prorenin receptor is essential for normal podocyte structure and function. J Am Soc Nephrol. 2011;22(12):2203–12. 10.1681/ASN.2011020202 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 200. Li C, Siragy HM: (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose. Am J Physiol Endocrinol Metab. 2015;309(3):E302–10. 10.1152/ajpendo.00603.2014 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 201. Chen J, Chen MX, Fogo AB, et al.: mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J Am Soc Nephrol. 2013;24(2):198–207. 10.1681/ASN.2012010101 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 202. Bechtel W, Helmstädter M, Balica J, et al.: Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J Am Soc Nephrol. 2013;24(5):727–43. 10.1681/ASN.2012070700 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 203. Weins A, Wong JS, Basgen JM, et al.: Dendrin ablation prolongs life span by delaying kidney failure. Am J Pathol. 2015;185(8):2143–57. 10.1016/j.ajpath.2015.04.011 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 204. Li X, Zhang X, Li X, et al.: The role of survivin in podocyte injury induced by puromycin aminonucleoside. Int J Mol Sci. 2014;15(4):6657–73. 10.3390/ijms15046657 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 205. Campbell KN, Wong JS, Gupta R, et al.: Yes-associated protein (YAP) promotes cell survival by inhibiting proapoptotic dendrin signaling. J Biol Chem. 2013;288(24):17057–62. 10.1074/jbc.C113.457390 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 206. Schwartzman M, Reginensi A, Wong JS, et al.: Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure. J Am Soc Nephrol. 2016;27(1):216–26. 10.1681/ASN.2014090916 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 207. Eremina V, Sood M, Haigh J, et al.: Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111(5):707–16. 10.1172/JCI17423 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 208. Eremina V, Cui S, Gerber H, et al.: Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol. 2006;17(3):724–35. 10.1681/ASN.2005080810 [PubMed] [CrossRef] [Google Scholar] 209. Kato H, Gruenwald A, Suh JH, et al.: Wnt/β-catenin pathway in podocytes integrates cell adhesion, differentiation, and survival. J Biol Chem. 2011;286(29):26003–15. 10.1074/jbc.M111.223164 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 210. Niranjan T, Bielesz B, Gruenwald A, et al.: The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med. 2008;14(3):290–8. 10.1038/nm1731 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 211. Kretzler M, Teixeira VP, Unschuld PG, et al.: Integrin-linked kinase as a candidate downstream effector in proteinuria. FASEB J. 2001;15(10):1843–5. 10.1096/fj.00-0832fje [PubMed] [CrossRef] [Google Scholar] 212. Teixeira Vde P, Blattner SM, Li M, et al.: Functional consequences of integrin-linked kinase activation in podocyte damage. Kidney Int. 2005;67(2):514–23. 10.1111/j.1523-1755.2005.67108.x [PubMed] [CrossRef] [Google Scholar] 213. Kang YS, Li Y, Dai C, et al.: Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria. Kidney Int. 2010;78(4):363–73. 10.1038/ki.2010.137 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 214. He JC, Husain M, Sunamoto M, et al.: Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways. J Clin Invest. 2004;114(5):643–51. 10.1172/JCI21004 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 215. Zuo Y, Matsusaka T, Zhong J, et al.: HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol. 2006;17(10):2832–43. 10.1681/ASN.2005080878 [PubMed] [CrossRef] [Google Scholar] 216. Waters AM, Wu MY, Onay T, et al.: Ectopic notch activation in developing podocytes causes glomerulosclerosis. J Am Soc Nephrol. 2008;19(6):1139–57. 10.1681/ASN.2007050596 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 217. Wasik AA, Polianskyte-Prause Z, Dong MQ, et al.: Septin 7 forms a complex with CD2AP and nephrin and regulates glucose transporter trafficking. Mol Biol Cell. 2012;23(17):3370–9. 10.1091/mbc.E11-12-1010 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 218. Schiffer M, Bitzer M, Roberts IS, et al.: Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001;108(8):807–16. 10.1172/JCI12367 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 219. Inoki K, Mori H, Wang J, et al.: mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181–96. 10.1172/JCI44771 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 220. Dai C, Stolz DB, Kiss LP, et al.: Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol. 2009;20(9):1997–2008. 10.1681/ASN.2009010019 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 221. Canaud G, Bienaimé F, Viau A, et al.: AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med. 2013;19(10):1288–96. 10.1038/nm.3313 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 222. Yang Y, Guo L, Blattner SM, et al.: Formation and phosphorylation of the PINCH-1-integrin linked kinase-alpha-parvin complex are important for regulation of renal glomerular podocyte adhesion, architecture, and survival. J Am Soc Nephrol. 2005;16(7):1966–76. 10.1681/ASN.2004121112 [PubMed] [CrossRef] [Google Scholar] 223. Rüster C, Franke S, Wenzel U, et al.: Podocytes of AT2 receptor knockout mice are protected from angiotensin II-mediated RAGE induction. Am J Nephrol. 2011;34(4):309–17. 10.1159/000329321 [PubMed] [CrossRef] [Google Scholar] 224. Heikkilä E, Juhila J, Lassila M, et al.: beta-Catenin mediates adriamycin-induced albuminuria and podocyte injury in adult mouse kidneys. Nephrol Dial Transplant. 2010;25(8):2437–46. 10.1093/ndt/gfq076 [PubMed] [CrossRef] [Google Scholar] 225. Jiang L, Xu L, Song Y, et al.: Calmodulin-dependent protein kinase II/cAMP response element-binding protein/Wnt/β-catenin signaling cascade regulates angiotensin II-induced podocyte injury and albuminuria. J Biol Chem. 2013;288(32):23368–79. 10.1074/jbc.M113.460394 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 226. Lu T, He JC, Wang ZH, et al.: HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein. J Biol Chem. 2008;283(13):8173–82. 10.1074/jbc.M708920200 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 227. Welsh GI, Hale LJ, Eremina V, et al.: Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 2010;12(4):329–40. 10.1016/j.cmet.2010.08.015 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 228. Hale LJ, Welsh GI, Perks CM, et al.: Insulin-like growth factor-II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse. J Pathol. 2013;230(1):95–106. 10.1002/path.4165 [PubMed] [CrossRef] [Google Scholar] 229. Hale LJ, Hurcombe J, Lay A, et al.: Insulin directly stimulates VEGF-A production in the glomerular podocyte. Am J Physiol Renal Physiol. 2013;305(2):F182–8. 10.1152/ajprenal.00548.2012 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 230. Brähler S, Ising C, Hagmann H, et al.: Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. Am J Physiol Renal Physiol. 2012;303(10):F1473–85. 10.1152/ajprenal.00031.2012 [PubMed] [CrossRef] [Google Scholar] 231. Brähler S, Ising C, Barrera Aranda B, et al.: The NF-κB essential modulator (NEMO) controls podocyte cytoskeletal dynamics independently of NF-κB. Am J Physiol Renal Physiol. 2015;309(7):F617–26. 10.1152/ajprenal.00059.2015 [PubMed] [CrossRef] [Google Scholar] 232. Lin CL, Wang FS, Hsu YC, et al.: Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy. Diabetes. 2010;59(8):1915–25. 10.2337/db09-0663 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 233. El Machhour F, Keuylian Z, Kavvadas P, et al.: Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease. J Am Soc Nephrol. 2015;26(7):1561–75. 10.1681/ASN.2013090968 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 234. Saurus P, Kuusela S, Lehtonen E, et al.: Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway. Cell Death Dis. 2015;6:e1752. 10.1038/cddis.2015.125 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 235. Gödel M, Hartleben B, Herbach N, et al.: Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197–209. 10.1172/JCI44774 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 236. Hyvönen ME, Saurus P, Wasik A, et al.: Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes. Mol Cell Endocrinol. 2010;328(1–2):70–9. 10.1016/j.mce.2010.07.016 [PubMed] [CrossRef] [Google Scholar] 237. Das R, Xu S, Quan X, et al.: Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes. Am J Physiol Renal Physiol. 2014;306(2):F155–67. 10.1152/ajprenal.00438.2013 [PubMed] [CrossRef] [Google Scholar] 238. Feng X, Lu TC, Chuang PY, et al.: Reduction of Stat3 activity attenuates HIV-induced kidney injury. J Am Soc Nephrol. 2009;20(10):2138–46. 10.1681/ASN.2008080879 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 239. Dai Y, Gu L, Yuan W, et al.: Podocyte-specific deletion of signal transducer and activator of transcription 3 attenuates nephrotoxic serum-induced glomerulonephritis. Kidney Int. 2013;84(5):950–61. 10.1038/ki.2013.197 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 240. Abkhezr M, Dryer SE: STAT3 regulates steady-state expression of synaptopodin in cultured mouse podocytes. Mol Pharmacol. 2015;87(2):231–9. 10.1124/mol.114.094508 [PubMed] [CrossRef] [Google Scholar] 241. Chugh SS: Transcriptional regulation of podocyte disease. Transl Res. 2007;149(5):237–42. 10.1016/j.trsl.2007.01.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 242. Zhang SY, Kamal M, Dahan K, et al.: c-mip impairs podocyte proximal signaling and induces heavy proteinuria. Sci Signal. 2010;3(122):ra39. 10.1126/scisignal.2000678 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 243. Sendeyo K, Audard V, Zhang SY, et al.: Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy. Kidney Int. 2013;83(3):414–25. 10.1038/ki.2012.426 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 244. Takemoto M, He L, Norlin J, et al.: Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J. 2006;25(5):1160–74. 10.1038/sj.emboj.7601014 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 245. Brukamp K, Jim B, Moeller MJ, et al.: Hypoxia and podocyte-specific Vhlh deletion confer risk of glomerular disease. Am J Physiol Renal Physiol. 2007;293(4):F1397–407. 10.1152/ajprenal.00133.2007 [PubMed] [CrossRef] [Google Scholar] 246. Steenhard BM, Isom K, Stroganova L, et al.: Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen {alpha}1{alpha}2{alpha}1(IV), expression of neuroglobin, and proteinuria. Am J Pathol. 2010;177(1):84–96. 10.2353/ajpath.2010.090767 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 247. Ding M, Cui S, Li C, et al.: Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med. 2006;12(9):1081–7. 10.1038/nm1460 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 248. Mallipattu SK, Horne SJ, D'Agati V, et al.: Krüppel-like factor 6 regulates mitochondrial function in the kidney. J Clin Invest. 2015;125(3):1347–61. 10.1172/JCI77084 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 249. Chen H, Lun Y, Ovchinnikov D, et al.: Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet. 1998;19(1):51–5. 10.1038/ng0598-51 [PubMed] [CrossRef] [Google Scholar] 250. Morello R, Zhou G, Dreyer SD, et al.: Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome. Nat Genet. 2001;27(2):205–8. 10.1038/84853 [PubMed] [CrossRef] [Google Scholar] 251. Miner JH, Morello R, Andrews KL, et al.: Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation. J Clin Invest. 2002;109(8):1065–72. 10.1172/JCI13954 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 252. Rohr C, Prestel J, Heidet L, et al.: The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes. J Clin Invest. 2002;109(8):1073–82. 10.1172/JCI13961 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 253. Suleiman H, Heudobler D, Raschta AS, et al.: The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes. Dev Biol. 2007;304(2):701–12. 10.1016/j.ydbio.2007.01.020 [PubMed] [CrossRef] [Google Scholar] 254. Burghardt T, Kastner J, Suleiman H, et al.: LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys. J Am Soc Nephrol. 2013;24(11):1830–48. 10.1681/ASN.2012080788 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 255. Sadl V, Jin F, Yu J, et al.: The mouse Kreisler ( Krml1/MafB) segmentation gene is required for differentiation of glomerular visceral epithelial cells. Dev Biol. 2002;249(1):16–29. 10.1006/dbio.2002.0751 [PubMed] [CrossRef] [Google Scholar] 256. Moriguchi T, Hamada M, Morito N, et al.: MafB is essential for renal development and F4/80 expression in macrophages. Mol Cell Biol. 2006;26(15):5715–27. 10.1128/MCB.00001-06 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 257. Wang Y, Jarad G, Tripathi P, et al.: Activation of NFAT signaling in podocytes causes glomerulosclerosis. J Am Soc Nephrol. 2010;21(10):1657–66. 10.1681/ASN.2009121253 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 258. Nijenhuis T, Sloan AJ, Hoenderop JG, et al.: Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway. Am J Pathol. 2011;179(4):1719–32. 10.1016/j.ajpath.2011.06.033 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 259. Barua M, Stellacci E, Stella L, et al.: Mutations in PAX2 associate with adult-onset FSGS. J Am Soc Nephrol. 2014;25(9):1942–53. 10.1681/ASN.2013070686 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 260. Cui S, Li C, Ema M, et al.: Rapid isolation of glomeruli coupled with gene expression profiling identifies downstream targets in Pod1 knockout mice. J Am Soc Nephrol. 2005;16(11):3247–55. 10.1681/ASN.2005030278 [PubMed] [CrossRef] [Google Scholar] 261. Zhou Y, Kong X, Zhao P, et al.: Peroxisome proliferator-activated receptor-α is renoprotective in doxorubicin-induced glomerular injury. Kidney Int. 2011;79(12):1302–11. 10.1038/ki.2011.17 [PubMed] [CrossRef] [Google Scholar] 262. Matsui I, Ito T, Kurihara H, et al.: Snail, a transcriptional regulator, represses nephrin expression in glomerular epithelial cells of nephrotic rats. Lab Invest. 2007;87(3):273–83. 10.1038/labinvest.3700518 [PubMed] [CrossRef] [Google Scholar] 263. Buelli S, Rosanò L, Gagliardini E, et al.: β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury. J Am Soc Nephrol. 2014;25(3):523–33. 10.1681/ASN.2013040362 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 264. Ito S, Ikeda M, Takata A, et al.: Nephrotic syndrome and end-stage renal disease with WT1 mutation detected at 3 years. Pediatr Nephrol. 1999;13(9):790–1. 10.1007/s004670050702 [PubMed] [CrossRef] [Google Scholar] 265. Guo JK, Menke AL, Gubler MC, et al.: WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. Hum Mol Genet. 2002;11(6):651–9. 10.1093/hmg/11.6.651 [PubMed] [CrossRef] [Google Scholar] 266. Patek CE, Fleming S, Miles CG, et al.: Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis. Hum Mol Genet. 2003;12(18):2379–94. 10.1093/hmg/ddg240 [PubMed] [CrossRef] [Google Scholar] 267. Chau YY, Brownstein D, Mjoseng H, et al.: Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1. PLoS Genet. 2011;7(12):e1002404. 10.1371/journal.pgen.1002404 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 268. Hall G, Gbadegesin RA, Lavin P, et al.: A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS. J Am Soc Nephrol. 2015;26(4):831–43. 10.1681/ASN.2013101053 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 269. Kumar PA, Kotlyarevska K, Dejkhmaron P, et al.: Growth hormone (GH)-dependent expression of a natural antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) in the glomerular podocyte: a novel action of gh with implications for the pathogenesis of diabetic nephropathy. J Biol Chem. 2010;285(41):31148–56. 10.1074/jbc.M110.132332 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 270. Liu G, Clement LC, Kanwar YS, et al.: ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. J Biol Chem. 2006;281(51):39681–92. 10.1074/jbc.M606664200 [PubMed] [CrossRef] [Google Scholar] 271. Lin Y, Rao J, Zha XL, et al.: Angiopoietin-like 3 induces podocyte F-actin rearrangement through integrin α(V)β₃/FAK/PI3K pathway-mediated Rac1 activation. Biomed Res Int. 2013;2013: 135608. 10.1155/2013/135608 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 272. Fiorina P, Vergani A, Bassi R, et al.: Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol. 2014;25(7):1415–29. 10.1681/ASN.2013050518 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 273. Iglesias-de la Cruz MC, Ziyadeh FN, Isono M, et al.: Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int. 2002;62(3):901–13. 10.1046/j.1523-1755.2002.00528.x [PubMed] [CrossRef] [Google Scholar] 274. Han SY, Kang YS, Jee YH, et al.: High glucose and angiotensin II increase beta1 integrin and integrin-linked kinase synthesis in cultured mouse podocytes. Cell Tissue Res. 2006;323(2):321–32. 10.1007/s00441-005-0065-4 [PubMed] [CrossRef] [Google Scholar] 275. Ha TS: High glucose and advanced glycosylated end-products affect the expression of alpha-actinin-4 in glomerular epithelial cells. Nephrology (Carlton). 2006;11(5):435–41. 10.1111/j.1440-1797.2006.00668.x [PubMed] [CrossRef] [Google Scholar] 276. Kim NH, Rincon-Choles H, Bhandari B, et al.: Redox dependence of glomerular epithelial cell hypertrophy in response to glucose. Am J Physiol Renal Physiol. 2006;290(3):F741–51. 10.1152/ajprenal.00313.2005 [PubMed] [CrossRef] [Google Scholar] 277. De Petris L, Hruska KA, Chiechio S, et al.: Bone morphogenetic protein-7 delays podocyte injury due to high glucose. Nephrol Dial Transplant. 2007;22(12):3442–50. 10.1093/ndt/gfm503 [PubMed] [CrossRef] [Google Scholar] 278. Wei C, El Hindi S, Li J, et al.: Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011;17(8):952–60. 10.1038/nm.2411 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 279. Koukouritaki SB, Vardaki EA, Papakonstanti EA, et al.: TNF-alpha induces actin cytoskeleton reorganization in glomerular epithelial cells involving tyrosine phosphorylation of paxillin and focal adhesion kinase. Mol Med. 1999;5(6):382–92. [PMC free article] [PubMed] [Google Scholar] 280. Saito Y, Okamura M, Nakajima S, et al.: Suppression of nephrin expression by TNF-alpha via interfering with the cAMP-retinoic acid receptor pathway. Am J Physiol Renal Physiol. 2010;298(6):F1436–44. 10.1152/ajprenal.00512.2009 [PubMed] [CrossRef] [Google Scholar] 281. Bitzan M, Babayeva S, Vasudevan A, et al.: TNFα pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and β3 integrin activation. Pediatr Nephrol. 2012;27(12):2217–26. 10.1007/s00467-012-2163-3 [PubMed] [CrossRef] [Google Scholar] 282. Tian D, Jacobo SM, Billing D, et al.: Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci Signal. 2010;3(145):ra77. 10.1126/scisignal.2001200 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 283. Yoshida S, Nagase M, Shibata S, et al.: Podocyte injury induced by albumin overload in vivo and in vitro: involvement of TGF-beta and p38 MAPK. Nephron Exp Nephrol. 2008;108(3):e57–68. 10.1159/000124236 [PubMed] [CrossRef] [Google Scholar] 284. He F, Chen S, Wang H, et al.: Regulation of CD2-associated protein influences podocyte endoplasmic reticulum stress-mediated apoptosis induced by albumin overload. Gene. 2011;484(1–2):18–25. 10.1016/j.gene.2011.05.025 [PubMed] [CrossRef] [Google Scholar] 285. Okamura K, Dummer P, Kopp J, et al.: Endocytosis of albumin by podocytes elicits an inflammatory response and induces apoptotic cell death. PLoS One. 2013;8(1):e54817. 10.1371/journal.pone.0054817 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 286. Shibata S, Nagase M, Yoshida S, et al.: Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49(2):355–64. 10.1161/01.HYP.0000255636.11931.a2 [PubMed] [CrossRef] [Google Scholar] 287. Zhu C, Huang S, Yuan Y, et al.: Mitochondrial dysfunction mediates aldosterone-induced podocyte damage: a therapeutic target of PPARγ. Am J Pathol. 2011;178(5):2020–31. 10.1016/j.ajpath.2011.01.029 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 288. Su M, Dhoopun AR, Yuan Y, et al.: Mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury. Am J Physiol Renal Physiol. 2013;305(4):F520–31. 10.1152/ajprenal.00570.2012 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 289. Dai R, Lin Y, Liu H, et al.: A vital role for Angptl3 in the PAN-induced podocyte loss by affecting detachment and apoptosis in vitro. BMC Nephrol. 2015;16:38. 10.1186/s12882-015-0034-4 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 290. Ding G, Reddy K, Kapasi AA, et al.: Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am J Physiol Renal Physiol. 2002;283(1):F173–80. 10.1152/ajprenal.00240.2001 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 291. Jia J, Ding G, Zhu J, et al.: Angiotensin II infusion induces nephrin expression changes and podocyte apoptosis. Am J Nephrol. 2008;28(3):500–7. 10.1159/000113538 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 292. Zhang H, Ding J, Fan Q, et al.: TRPC6 up-regulation in Ang II-induced podocyte apoptosis might result from ERK activation and NF-kappaB translocation. Exp Biol Med (Maywood). 2009;234(9):1029–36. 10.3181/0901-RM-11 [PubMed] [CrossRef] [Google Scholar] 293. Ren Z, Liang W, Chen C, et al.: Angiotensin II induces nephrin dephosphorylation and podocyte injury: role of caveolin-1. Cell Signal. 2012;24(2):443–50. 10.1016/j.cellsig.2011.09.022 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 294. Sanchez-Niño MD, Sanz AB, Sanchez-Lopez E, et al.: HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II. Lab Invest. 2012;92(1):32–45. 10.1038/labinvest.2011.138 [PubMed] [CrossRef] [Google Scholar] 295. Sieber J, Lindenmeyer MT, Kampe K, et al.: Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids. Am J Physiol Renal Physiol. 2010;299(4):F821–9. 10.1152/ajprenal.00196.2010 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 296. Sieber J, Weins A, Kampe K, et al.: Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2. Am J Pathol. 2013;183(3):735–44. 10.1016/j.ajpath.2013.05.023 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 297. Kampe K, Sieber J, Orellana JM, et al.: Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. Am J Physiol Renal Physiol. 2014;306(4):F401–9. 10.1152/ajprenal.00454.2013 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 298. Susztak K, Raff AC, Schiffer M, et al.: Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006;55(1):225–33. 10.2337/diabetes.55.01.06.db05-0894 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 299. Peters I, Tossidou I, Achenbach J, et al.: IGF-binding protein-3 modulates TGF-beta/BMP-signaling in glomerular podocytes. J Am Soc Nephrol. 2006;17(6):1644–56. 10.1681/ASN.2005111209 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 300. Bussolati B, Deregibus MC, Fonsato V, et al.: Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway. J Am Soc Nephrol. 2005;16(7):1936–47. 10.1681/ASN.2004080629 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 301. Schiffer M, Mundel P, Shaw AS, et al.: A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J Biol Chem. 2004;279(35):37004–12. 10.1074/jbc.M403534200 [PubMed] [CrossRef] [Google Scholar] 302. Wada T, Pippin JW, Terada Y, et al.: The cyclin-dependent kinase inhibitor p21 is required for TGF-beta1-induced podocyte apoptosis. Kidney Int. 2005;68(4):1618–29. 10.1111/j.1523-1755.2005.00574.x [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 303. Wu DT, Bitzer M, Ju W, et al.: TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J Am Soc Nephrol. 2005;16(11):3211–21. 10.1681/ASN.2004121055 [PubMed] [CrossRef] [Google Scholar] 304. Jung KY, Chen K, Kretzler M, et al.: TGF-beta1 regulates the PINCH-1-integrin-linked kinase-alpha-parvin complex in glomerular cells. J Am Soc Nephrol. 2007;18(1):66–73. 10.1681/ASN.2006050421 [PubMed] [CrossRef] [Google Scholar] 305. Yadav A, Vallabu S, Arora S, et al.: ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol. 2010;299(2):C488–96. 10.1152/ajpcell.00424.2009 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 306. Ma T, Zhu J, Chen X, et al.: High glucose induces autophagy in podocytes. Exp Cell Res. 2013;319(6):779–89. 10.1016/j.yexcr.2013.01.018 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 307. Liu Y: New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 2010;21(2):212–22. 10.1681/ASN.2008121226 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 308. Li Y, Kang YS, Dai C, et al.: Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. Am J Pathol. 2008;172(2):299–308. 10.2353/ajpath.2008.070057 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 309. Husain M, Gusella GL, Klotman ME, et al.: HIV-1 Nef induces proliferation and anchorage-independent growth in podocytes. J Am Soc Nephrol. 2002;13(7):1806–15. 10.1097/01.ASN.0000019642.55998.69 [PubMed] [CrossRef] [Google Scholar] 310. Sunamoto M, Husain M, He JC, et al.: Critical role for Nef in HIV-1-induced podocyte dedifferentiation. Kidney Int. 2003;64(5):1695–701. 10.1046/j.1523-1755.2003.00283.x [PubMed] [CrossRef] [Google Scholar] 311. Bruggeman LA, Drawz PE, Kahoud N, et al.: TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α. Lab Invest. 2011;91(3):413–25. 10.1038/labinvest.2010.199 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 312. Clement LC, Macé C, Avila-Casado C, et al.: Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med. 2014;20(1):37–46. 10.1038/nm.3396 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 313. Isermann B, Vinnikov IA, Madhusudhan T, et al.: Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med. 2007;13(11):1349–58. 10.1038/nm1667 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 314. Madhusudhan T, Wang H, Straub BK, et al.: Cytoprotective signaling by activated protein C requires protease-activated receptor-3 in podocytes. Blood. 2012;119(3):874–83. 10.1182/blood-2011-07-365973 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 315. Mitu GM, Wang S, Hirschberg R: BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am J Physiol Renal Physiol. 2007;293(5):F1641–8. 10.1152/ajprenal.00179.2007 [PubMed] [CrossRef] [Google Scholar] 316. Foster RR, Hole R, Anderson K, et al.: Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes. Am J Physiol Renal Physiol. 2003;284(6):F1263–73. 10.1152/ajprenal.00276.2002 [PubMed] [CrossRef] [Google Scholar] 317. Foster RR, Saleem MA, Mathieson PW, et al.: Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol Renal Physiol. 2005;288(1):F48–57. 10.1152/ajprenal.00146.2004 [PubMed] [CrossRef] [Google Scholar] 318. Müller-Deile J, Worthmann K, Saleem M, et al.: The balance of autocrine VEGF-A and VEGF-C determines podocyte survival. Am J Physiol Renal Physiol. 2009;297(6):F1656–67. 10.1152/ajprenal.00275.2009 [PubMed] [CrossRef] [Google Scholar] 319. Foster RR, Satchell SC, Seckley J, et al.: VEGF-C promotes survival in podocytes. Am J Physiol Renal Physiol. 2006;291(1):F196–207. 10.1152/ajprenal.00431.2005 [PubMed] [CrossRef] [Google Scholar] 320. Barisoni L, Schnaper HW, Kopp JB: A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin J Am Soc Nephrol. 2007;2(3):529–42. 10.2215/CJN.04121206 [PubMed] [CrossRef] [Google Scholar] 321. Chiang C, Inagi R: Glomerular diseases: genetic causes and future therapeutics. Nat Rev Nephrol. 2010;6(9):539–54. 10.1038/nrneph.2010.103 [PubMed] [CrossRef] [Google Scholar] 322. Smeets B, Moeller MJ: Parietal epithelial cells and podocytes in glomerular diseases. Semin Nephrol. 2012;32(4):357–67. 10.1016/j.semnephrol.2012.06.007 [PubMed] [CrossRef] [Google Scholar] 323. Pollak MR: The genetic basis of FSGS and steroid-resistant nephrosis. Semin Nephrol. 2003;23(2):141–6. 10.1053/snep.2003.50014 [PubMed] [CrossRef] [Google Scholar] 324. Löwik MM, Groenen PJ, Levtchenko EN, et al.: Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis--a review. Eur J Pediatr. 2009;168(11):1291–304. 10.1007/s00431-009-1017-x [PMC free article] [PubMed] [CrossRef] [Google Scholar] 325. Kuppe C, Gröne HJ, Ostendorf T, et al.: Common histological patterns in glomerular epithelial cells in secondary focal segmental glomerulosclerosis. Kidney Int. 2015;88(5):990–8. 10.1038/ki.2015.116 [PubMed] [CrossRef] [Google Scholar] 326. Wiggins RC: The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int. 2007;71(12):1205–14. 10.1038/sj.ki.5002222 [PubMed] [CrossRef] [Google Scholar] 327. Fukuda A, Chowdhury MA, Venkatareddy MP, et al.: Growth-dependent podocyte failure causes glomerulosclerosis. J Am Soc Nephrol. 2012;23(8):1351–63. 10.1681/ASN.2012030271 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 328. Kriz W, LeHir M: Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int. 2005;67(2):404–19. 10.1111/j.1523-1755.2005.67097.x [PubMed] [CrossRef] [Google Scholar] 329. Savin VJ, Sharma R, Sharma M, et al.: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med. 1996;334(14):878–83. 10.1056/NEJM199604043341402 [PubMed] [CrossRef] [Google Scholar] 330. McCarthy ET, Sharma M, Savin VJ: Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010;5(11):2115–21. 10.2215/CJN.03800609 [PubMed] [CrossRef] [Google Scholar] 331. Bose B, Cattran D: Glomerular diseases: FSGS. Clin J Am Soc Nephrol. 2014;9(3):626–32. 10.2215/CJN.05810513 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 332. Hayek SS, Sever S, Ko YA, et al.: Soluble Urokinase Receptor and Chronic Kidney Disease. N Engl J Med. 2015;373(20):1916–25. 10.1056/NEJMoa1506362 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 333. Regele HM, Fillipovic E, Langer B, et al.: Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis. J Am Soc Nephrol. 2000;11(3):403–12. [PubMed] [Google Scholar] 334. Chugh SS, Clement LC, Macé C: New insights into human minimal change disease: lessons from animal models. Am J Kidney Dis. 2012;59(2):284–92. 10.1053/j.ajkd.2011.07.024 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 335. Yang Y, Gubler M, Beaufils H: Dysregulation of podocyte phenotype in idiopathic collapsing glomerulopathy and HIV-associated nephropathy. Nephron. 2002;91(3):416–23. 10.1159/000064281 [PubMed] [CrossRef] [Google Scholar] 336. Medapalli RK, He JC, Klotman PE: HIV-associated nephropathy: pathogenesis. Curr Opin Nephrol Hypertens. 2011;20(3):306–11. 10.1097/MNH.0b013e328345359a [PMC free article] [PubMed] [CrossRef] [Google Scholar] 337. Laurinavicius A, Rennke HG: Collapsing glomerulopathy--a new pattern of renal injury. Semin Diagn Pathol. 2002;19(3):106–15. [PubMed] [Google Scholar] 338. Barri YM, Munshi NC, Sukumalchantra S, et al.: Podocyte injury associated glomerulopathies induced by pamidronate. Kidney Int. 2004;65(2):634–41. 10.1111/j.1523-1755.2004.00426.x [PubMed] [CrossRef] [Google Scholar] 339. Albaqumi M, Soos TJ, Barisoni L, et al.: Collapsing glomerulopathy. J Am Soc Nephrol. 2006;17(10):2854–63. 10.1681/ASN.2006030225 [PubMed] [CrossRef] [Google Scholar] 340. Detwiler RK, Falk RJ, Hogan SL, et al.: Collapsing glomerulopathy: a clinically and pathologically distinct variant of focal segmental glomerulosclerosis. Kidney Int. 1994;45(5):1416–24. 10.1038/ki.1994.185 [PubMed] [CrossRef] [Google Scholar] 341. Atta MG, Gallant JE, Rahman MH, et al.: Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. 2006;21(10):2809–13. 10.1093/ndt/gfl337 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 342. Gherardi D, D'Agati V, Chu TH, et al.: Reversal of collapsing glomerulopathy in mice with the cyclin-dependent kinase inhibitor CYC202. J Am Soc Nephrol. 2004;15(5):1212–22. 10.1097/01.ASN.0000124672.41036.F4 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 343. Vaughan MR, Pippin JW, Griffin SV, et al.: ATRA induces podocyte differentiation and alters nephrin and podocin expression in vitro and in vivo. Kidney Int. 2005;68(1):133–44. 10.1111/j.1523-1755.2005.00387.x [PubMed] [CrossRef] [Google Scholar] 344. Albaqumi M, Barisoni L: Current views on collapsing glomerulopathy. J Am Soc Nephrol. 2008;19(7):1276–81. 10.1681/ASN.2007080926 [PubMed] [CrossRef] [Google Scholar] 345. D'Amico G: The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med. 1987;64(245):709–27. [PubMed] [Google Scholar] 346. Wyatt RJ, Julian BA: IgA nephropathy. N Engl J Med. 2013;368(25):2402–14. 10.1056/NEJMra1206793 [PubMed] [CrossRef] [Google Scholar] 347. Lemley KV, Lafayette RA, Safai M, et al.: Podocytopenia and disease severity in IgA nephropathy. Kidney Int. 2002;61(4):1475–85. 10.1046/j.1523-1755.2002.00269.x [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 348. Lai KN, Leung JC, Chan LY, et al.: Activation of podocytes by mesangial-derived TNF-alpha: glomerulo-podocytic communication in IgA nephropathy. Am J Physiol Renal Physiol. 2008;294(4):F945–55. 10.1152/ajprenal.00423.2007 [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 349. Gagliardini E, Benigni A, Tomasoni S, et al.: Targeted downregulation of extracellular nephrin in human IgA nephropathy. Am J Nephrol. 2003;23(4):277–86. 10.1159/000072281 [PubMed] [CrossRef] [Google Scholar] 350. Kramer H: Obesity and chronic kidney disease. Contrib Nephrol. 2006;151:1–18. 10.1159/000095315 [PubMed] [CrossRef] [Google Scholar] 351. Zhou X, Hurst RD, Templeton D, et al.: High glucose alters actin assembly in glomerular mesangial and epithelial cells. Lab Invest. 1995;73(3):372–83. [PubMed] [Google Scholar] 352. Chen HM, Liu ZH, Zeng CH, et al.: Podocyte lesions in patients with obesity-related glomerulopathy. Am J Kidney Dis. 2006;48(5):772–9. 10.1053/j.ajkd.2006.07.025 [PubMed] [CrossRef] [Google Scholar] 353. Griffin SV, Petermann AT, Durvasula RV, et al.: Podocyte proliferation and differentiation in glomerular disease: role of cell-cycle regulatory proteins. Nephrol Dial Transplant. 2003;18(Suppl 6):vi8–13. 10.1093/ndt/gfg1069 [PubMed] [CrossRef] [Google Scholar] 354. Kriz W: Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech. 2002;57(4):189–95. 10.1002/jemt.10072 [PubMed] [CrossRef] [Google Scholar] 355. Kikuchi M, Wickman L, Hodgin JB, et al.: Podometrics as a Potential Clinical Tool for Glomerular Disease Management. Semin Nephrol. 2015;35(3):245–55. 10.1016/j.semnephrol.2015.04.004 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 356. Reiser J, Gupta V, Kistler AD: Toward the development of podocyte-specific drugs. Kidney Int. 2010;77(8):662–8. 10.1038/ki.2009.559 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 357. Chugh SS, Macé C, Clement LC, et al.: Angiopoietin-like 4 based therapeutics for proteinuria and kidney disease. Front Pharmacol. 2014;5:23. 10.3389/fphar.2014.00023 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 358. Fornoni A, Sageshima J, Wei C, et al.: Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med. 2011;3(85):85ra46. 10.1126/scitranslmed.3002231 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 359. Yu CC, Fornoni A, Weins A, et al.: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2013;369(25):2416–23. 10.1056/NEJMoa1304572 [PMC free article] [PubMed] [CrossRef] [Google Scholar] F1000 Recommendation 360. Benigni A, Gagliardini E, Remuzzi G: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2014;370(13):1261–3. 10.1056/NEJMc1400502#SA1 [PubMed] [CrossRef] [] 361. Alachkar N, Carter-Monroe N, Reiser J: Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2014;370(13):1263–4. 10.1056/NEJMc1400502#SA2 [PubMed] [CrossRef] [] 362. Salant DJ: Podocyte Expression of B7-1/CD80: Is it a Reliable Biomarker for the Treatment of Proteinuric Kidney Diseases with Abatacept? J Am Soc Nephrol. 2015; pii: ASN.2015080947. 10.1681/ASN.2015080947 [PMC free article] [PubMed] [CrossRef] [Google Scholar] 363. Schiffer M, Teng B, Gu C, et al.: Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. |
