The podocyte's response to injury: Role in proteinuria and glomerulosclerosis
2006; Elsevier BV; Volume: 69; Issue: 12 Linguagem: Inglês
10.1038/sj.ki.5000410
ISSN1523-1755
Autores Tópico(s)Genetic and Kidney Cyst Diseases
ResumoThe terminally differentiated podocyte, also called glomerular visceral epithelial cell, are highly specialized cells. They function as a critical size and charge barrier to prevent proteinuria. Podocytes are injured in diabetic and non-diabetic renal diseases. The clinical signature of podocyte injury is proteinuria, with or without loss of renal function owing to glomerulosclerosis. There is an exciting and expanding literature showing that hereditary, congenital, or acquired abnormalities in the molecular anatomy of podocytes leads to proteinuria, and at times, glomerulosclerosis. The change in podocyte shape, called effacement, is not simply a passive process following injury, but is owing to a complex interplay of proteins that comprise the molecular anatomy of the different protein domains of podocytes. These will be discussed in this review. Recent studies have also highlighted that a reduction in podocyte number directly causes proteinuria and glomerulosclerosis. This is owing to several factors, including the relative inability for these cells to proliferate, detachment, and apoptosis. The mechanisms of these events are being elucidated, and are discussed in this review. It is the hope that by delineating the events following injury to podocytes, therapies might be developed to reduce the burden of proteinuric renal diseases. The terminally differentiated podocyte, also called glomerular visceral epithelial cell, are highly specialized cells. They function as a critical size and charge barrier to prevent proteinuria. Podocytes are injured in diabetic and non-diabetic renal diseases. The clinical signature of podocyte injury is proteinuria, with or without loss of renal function owing to glomerulosclerosis. There is an exciting and expanding literature showing that hereditary, congenital, or acquired abnormalities in the molecular anatomy of podocytes leads to proteinuria, and at times, glomerulosclerosis. The change in podocyte shape, called effacement, is not simply a passive process following injury, but is owing to a complex interplay of proteins that comprise the molecular anatomy of the different protein domains of podocytes. These will be discussed in this review. Recent studies have also highlighted that a reduction in podocyte number directly causes proteinuria and glomerulosclerosis. This is owing to several factors, including the relative inability for these cells to proliferate, detachment, and apoptosis. The mechanisms of these events are being elucidated, and are discussed in this review. It is the hope that by delineating the events following injury to podocytes, therapies might be developed to reduce the burden of proteinuric renal diseases. Diabetic and non-diabetic glomerular diseases remain the major cause of chronic and end-stage renal disease. What makes the glomerulus fascinating, yet clinically challenging, is that there are four resident cell types that are potentially injured in different disease states. These include mesangial, endothelial, visceral epithelial (also called podocytes), and parietal epithelial cells. We and others classify glomerular disease based on which resident glomerular cell type is injured, as this provides a better understanding of why patients present clinically with nephritic and/or nephrotic syndromes. Diseases of mesangial cells (such as immunoglobulin (Ig)A nephropathy, lupus nephritis) and endothelial cells (such as thrombotic microangiopathy, lupus nephritis, mesangioproliferative glomerulonephritis, and others) typically cause nephritic syndrome. The parietal epithelial cell is a significant component of crescents in most forms of crescentic glomerulonephritis. In contrast, diseases of podocytes typically present with proteinuria, with or without nephrotic syndrome (Table 1). It should be noted that not all cases of nephrotic range proteinuria are owing to podocyte diseases, because the glomerular filtration barrier also comprises the glomerular endothelial cell (GEN) and glomerular basement membrane (GBM). Damage to these glomerular structures may therefore also present with nephrotic-range proteinuria, such as anti-GBM disease or thrombotic microangiopathy, respectively.Table 1Diseases of the podocytePodocyte diseaseCause of injuryMechanism/mediatorMembranous nephropathyAnti-podocyte antibodiesC5b-9Minimal change diseaseT cell mediatedNot well definedClassic FSGSHereditaryα-Actinin-4 mutationPodocin mutationCD2AP haploinsufficiencyIncreased Pgc owing to:Podocyte stress–tension• Obesity• Diabetes• Hypertension• Reduced nephron number↓Podocyte numberApoptosisDetachmentLack of proliferationDNA damageHypertrophyCirculating factorsPermeability factor(s)Sporadic diseaseα-Actinin-4 mutationPodocin mutationCellular/collapsing FSGSInfectionsHIVParvo B19?DrugsPamidronateInterferonDiabetic nephropathyMetabolicHyperglycemiaIncreased PgcPodocyte stress–tensionAmyloidAmyloid protein depositionAmyloid spicules directly injure podocyteMPGNDeposition of antigen–antibody complexesSplitting of GBMPodocyte effacementFSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane. Open table in a new tab FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane. The focus of this forum is on podocytes, specifically how they respond to injury or damage, and how these events lead proteinuria and glomerulosclerosis. Podocytes are highly specialized, terminally differentiated epithelial cells, with a quiescent phenotype.1.Shankland S.J. Al-Douahji M. Cell cycle regulatory proteins in glomerular disease.Exp Nephrol. 1999; 7: 207-211Crossref PubMed Google Scholar Podocytes derive embryonically from mesenchymal cells.2.Saxen L. Organogenesis of the Kidney. Cambridge University Press, Cambridge1997Google Scholar Each mature podocyte has distinct anatomical, and therefore functional, components.3.Mundel P. Kriz W. Structure and function of podocytes: an update [Review article].Anat Embryol. 1995; 192: 385-397Crossref PubMed Scopus (198) Google Scholar The cell body is at the center of the cell, and essentially lies in the urinary space. Herein lies the cell's nucleus, Golgi apparatus, and other cell machinery such as endoplasmic reticulum and mitochondria. From the cell body arise long primary processes, the ends of which contains foot processes. Foot processes in turn attach to the underlying GBM via integrins4.Adler S. Chen X. Anti-Fx1A antibody recognizes a beta-1-integrin on glomerular epithelial cells and inhibits adhesion and growth.Am J Physiol. 1992; 262: F770-F776PubMed Google Scholar and dystroglycans,5.Kojima K. Kerjaschki D. Is podocyte shape controlled by the dystroglycan complex?.Nephrol Dial Transplant. 2002; 17: 23-24Crossref PubMed Google Scholar thereby anchoring this cell to the glomerular tuft. Foot processes from neighboring podocytes overlap (interdigitate). The ‘filtration slit’ formed between adjacent interdigitating podocyte foot processes is a highly specialized gap junction called the slit diaphragm, which forms the major size barrier to protein leakage (see later for more details in slit diaphragm proteins). Podocytes are polarized cells. Their unique shape is owing to an abundantly rich actin cytoskeleton, which serves as the podocyte's ‘backbone’.6.Mundel P. Reiser J. Zuniga Mejia Borja A. et al.Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines.Exp Cell Res. 1997; 236: 248-258Crossref PubMed Scopus (490) Google Scholar The actin cytoskeleton also enables podocytes to continually and dynamically alter shape, and also serves as a static function. The cytoskeleton comprises three distinct ultrastructural elements: (i) microfilaments (7–9 nm diameter), intermediate filaments (10 nm), and microtubules (24 nm). Microfilaments are the predominant cytoskeletal constituents of the foot process, and contain a dense network of F-actin and myosin. As will be discussed later, there are several actin-binding proteins such as synaptopodin7.Mundel P. Heid H.W. Mundel T.M. et al.Synaptodopodin: an actin-associated protein in telencephalic dendrites and renal podocytes.J Cell Biol. 1997; 139: 193-204Crossref PubMed Scopus (354) Google Scholar and α-actinin-48.Kaplan J.M. Kim S.H. North K.N. et al.Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.Nat Genet. 2000; 24: 251-256Crossref PubMed Scopus (795) Google Scholar in podocytes, which are important in maintaining podocyte shape. The actin cytoskeleton is linked with other proteins. Kerjaschki9.Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis.J Clin Invest. 2001; 108: 1583-1587Crossref PubMed Scopus (212) Google Scholar has classified podocytes into apical, basal, and junctional cell membrane domains, based on the molecular anatomy at each site. The junctional domain of proteins comprises those proteins comprising slit diaphragm proteins. Tryggvason was the first to discover nephrin,10.Ruotsalainen V. Ljungberg P. Wartiovaara J. et al.Nephrin is specifically located at the slit diaphragm of glomerular podocytes.Proc Natl Acad Sci USA. 1999; 96: 7962-7967Crossref PubMed Scopus (447) Google Scholar a member of the Ig superfamily, as one of the now increasing number of complex slit diaphragm proteins. The cytoplasmic tail of nephrin binds to podocin.11.Roselli S. Boute N. Sich M. et al.Podocin localizes in the kidney to the slit diphragm area.Am J Pathol. 2002; 160: 131-139Abstract Full Text Full Text PDF PubMed Google Scholar, 12.Huber T.B. Kottgen M. Schilling B. et al.Interaction with podocin facilitates nehrin signaling.J Biol Chem. 2001; 276: 4153-41546Google Scholar, 13.Schwarz K. Simons M. Reiser J. et al.Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin.J Clin Invest. 2001; 108: 1621-1629Crossref PubMed Scopus (377) Google Scholar Nephrin also interacts with and localizes to CD2AP.14.Shih N.Y. Li J. Cotran R. et al.CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain.Am J Pathol. 2001; 159: 2303-2308Abstract Full Text Full Text PDF PubMed Google Scholar, 15.Li C. Ruotsalainen V. Tryggvason K. et al.CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere.Am J Physiol Renal Physiol. 2000; 279: F785-F792PubMed Google Scholar More recently, another Ig superfamily of proteins have been identified called Neph-1, which interacts with nephrin, podocin, and FAT1.16.Sellin L. Huber T.B. Gerke P. et al.NEPH1 defines a novel family of podocin interacting proteins.FASEB J. 2003; 17: 115-117Crossref PubMed Google Scholar, 17.Benzing T. Signaling at the slit diaphragm.J Am Soc Nephrol. 2004; 15: 1382-1391Crossref PubMed Scopus (151) Google Scholar Other slit diaphragm proteins include ZO-1, Neph-2 and -3, and densin.18.Ahola H. Heikkila E. Astrom E. et al.A novel protein, densin, expressed by glomerular podocytes.J Am Soc Nephrol. 2003; 14: 1731-1737Crossref PubMed Scopus (55) Google Scholar By forming the only connection between adjacent podocytes, the slit diaphragm limits protein leakage by acting as a size barrier, analogous to a sieve. One is also left speculating that the slit may also function as a charge barrier, as some of these proteins are phosphorylated. As will be discussed later, certain slit diaphragm proteins actively participate in podocyte signaling, thereby enabling the slit to communicate with other podocyte proteins such as the actin cytoskeleton. The apical membrane domain of podocytes is negatively charged, owing to the presence of the surface anionic proteins podocalyxin,19.Kerjaschki D. Sharkey D. Farquhar M.G. Identification and characterization of podocalyxin – the major sialoprotein of the renal glomerular epithelial cell.J Cell Biol. 1984; 98: 1591-1596Crossref PubMed Google Scholar podoplanin,20.Matsui K. Breitender-Geleff S. Soleiman A. et al.Podoplanin, a novel 43-kDa membrane protein, controls the shape of podocytes.Nephrol Dial Transplant. 1999; 14: 9-11Crossref PubMed Google Scholar and podoendin. This serves two functions. First, negative charge limits the passage of albumin (also negatively charged). Second, adjacent podocytes maintain separation by anion charge. The basal domain is required to anchor podocyte to the underlying GBM. α3β1 integrin21.Kriedberg J.A. Donovan M.J. Goldstein S.L. et al.Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis.Development. 1996; 122: 3537-3547PubMed Google Scholar and α- and β-dystroglycans22.Raats C.J. Van Den Born J. Baker M.A. et al.Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies.Am J pathol. 2000; 156: 1749-1765Abstract Full Text Full Text PDF PubMed Google Scholar serve this function, and connect the body of the podocyte to certain matrix proteins within the GBM. The complex architecture of constitutive proteins is required for the highly specialized functions of podocytes, which includes (i) a size barrier to protein; (ii) charge barrier to protein; (iii) maintenance of the capillary loop shape; (iv) counteracting the intraglomerular pressure; (v) synthesis and maintenance of the GBM; (vi) production and secretion of vascular endothelial growth factor (VEGF) required for GEN integrity. Therefore, it comes as little surprise that perturbations in one or more of these functions following podocyte injury underlies the signature clinical findings including marked proteinuria, typically nephrotic range, and often a decrease in renal function with elevated creatinine, both of which will be discussed in detail below. From a clinical prospective, the predominant causes of nephrotic range proteinuria in adults owing to podocyte damage include focal segmental glomerulosclerosis (FSGS), membranous nephropathy, minimal change disease, membranoproliferative glomerulonephritis, amyloid, and diabetic nephropathy. However, for the most part, these diseases are named according to histologic descriptions of each disease, and do not inform one of the causes and mechanisms of each disease entity. The causes of podocyte injury in each disease entity are shown in Table 1, and each will be described briefly. The classification of podocyte injury preferred by the author is to classify podocyte diseases into congenital, hereditary, and acquired causes. The latter is further divided into immune and non-immune causes. Congenital causes include abnormalities in structural podocyte proteins, and this is best exemplified by congenital nephrotic syndrome of the Finnish type. In this disorder, there are several different mutations in nephrin leading to a loss of normal podocyte function, resulting in the onset of fetal proteinuria.23.Tryggvason K. Ruotsalainen V. Wartiovaara J. Discovery of the congenital nephrotic syndrome gene discloses the structure of the mysterious molecular sieve of the kidney.Int J Dev Biol. 1999; 43: 445-451PubMed Google Scholar, 24.Kestila M. Ienkkeri U. Mannikko M. et al.Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome.Mol Cell. 1998; 1: 575-582Abstract Full Text Full Text PDF PubMed Google Scholar Recent studies have shown that another congenital cause of podocyte damage is the development of maternal antibodies to neutral endopeptidase25.Ronco P. Debiec H. Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization.J Am Soc Nephrol. 2005; 16: 1205-1213Crossref PubMed Scopus (78) Google Scholar and metallomembrane endopeptidase26.Debiec H. Nauta J. Coulet F. et al.Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies.Lancet. 2004; 364: 1252-1259Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar in mothers who are deficient in the enzyme. As the fetus has the neutral endopeptidase antigen and the mother does not, the mother develops antibodies to this antigen, which cross the materno–fetal circulation, and deposit in podocytes, giving rise to membranous nephropathy. Ronco and Debiec25.Ronco P. Debiec H. Molecular pathomechanisms of membranous nephropathy: from Heymann nephritis to alloimmunization.J Am Soc Nephrol. 2005; 16: 1205-1213Crossref PubMed Scopus (78) Google Scholar have recently shown a role for anti-neutral endopeptidase antibodies in certain cases of childhood onset membranous nephropathy. These antibodies are acquired in utero, and thus can be considered congenital. One of nephrin's binding partners, CD2AP gives rise to proteinuria in patients who have CD2AP haploinsufficiency.27.Kim J.M. Wu H. Green G. et al.CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility.Science. 2003; 300: 1298-1300Crossref PubMed Scopus (307) Google Scholar There are several hereditary causes of podocyte injury and proteinuria, and these typically include mutations in podocyte-specific proteins, of which mutations in α-actinin-4 and podocin are best defined. Pollak and co-workers identified that mutations in the podocyte actin-associated protein, α-actinin-4, causes autosomal-dominant FSGS.8.Kaplan J.M. Kim S.H. North K.N. et al.Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.Nat Genet. 2000; 24: 251-256Crossref PubMed Scopus (795) Google Scholar Proteinuria typically develops in adulthood. Antignac and co-workers were the first to report that mutations in the slit diaphragm protein podocin causes autosomal-recessive steroid-resistant nephrotic syndrome and FSGS in children.28.Boute N. Roselli S. Benessy F. et al.NPHS2 encoding the glomerular proteins podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.Nat Genet. 2000; 24: 349-354Crossref PubMed Scopus (870) Google Scholar More recently, mutations in TRPC6, a newly discovered slit diaphragm protein, also leads to hereditary proteinuria.29.Winn M.P. Conlon P.J. Lynn K.L. et al.A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.Science. 2005; 308: 1801-1804Crossref PubMed Scopus (550) Google Scholar, 30.Reiser J. Polu K.R. Moller C.C. et al.TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.Nat Genet. 2005; 37: 739-744Crossref PubMed Scopus (422) Google Scholar The majority of podocyte diseases are acquired, and these can be considered immune and non-immune mediated. The characteristic immune-mediated forms of podocyte injury are membranous nephropathy and minimal change disease, although one might also consider membranoproliferative glomerulonephritis associated with cryoglobulins as immune-mediated podocyte injury. The antibodies that cause ‘idiopathic’ membranous nephropathy remain elusive in man. Kerjaschki and Farquhar identified the Heymann nephritis antigenic complex, now called megalin, in rats as the autoantigenic target.31.Kerjaschki D. Neale T.J. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis).J Am Soc Nephrol. 1996; 7: 2518-2526Crossref PubMed Google Scholar Minimal change disease is considered immune-mediated because it is likely owing to an abnormality in T cells, although the precise mechanisms are not well defined. Non-immune causes of acquired podocyte injury are multiple. These include infectious causes such as HIV-associated nephropathy giving rise to the characteristic collapsing glomerulopathy owing to the local infection of podocytes by the HIV virus.32.Ross M.J. Klotman P.E. Recent progress in HIV-associated nephropathy.J Am Soc Nephrol. 2002; 13: 2997-3004Crossref PubMed Scopus (101) Google Scholar Many speculate that Parvo B19 virus may also induce collapsing glomerulopathy in HIV-negative patients. The prototypical metabolic cause of podocyte injury is diabetes. Although diabetic nephropathy has long been considered a mesangial disease, it is also associated with significant podocyte injury (and hence marked proteinuria).33.Pagtalunan M.E. Miller P.L. Jumping-Eagle S. et al.Podocyte loss and progressive glomerular injury in type II diabetes.J Clin Invest. 1997; 99: 342-348Crossref PubMed Google Scholar There is an increasing body of literature showing that stress–tension, a result of increased intraglomerular pressure, causes podocyte injury.34.Durvasula R.V. Petermann A.T. Hiromura K. et al.Activation of a local tissue angiotensin system in podocytes by mechanical strain.Kidney Int. 2004; 65: 30-39Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 35.Endlich N. Kress K.R. Reiser J. et al.Podocytes respond to mechanical stress in vitro.J Am Soc Nephrol. 2001; 12: 413-422Crossref PubMed Google Scholar This is likely one of the final common pathways in systemic hypertension, diabetic nephropathy, the metabolic syndrome, and any cause of a reduced nephron number such as reflux nephropathy, or chronic glomerulopathies. Infiltrative diseases of podocytes are not common, and include amyloid, where studies have shown that individual amyloid spicules ‘project’ through the GBM, penetrating into the overlying podocytes. Finally, although the vast majority of slit diaphragm protein mutations are congenital or hereditary, recent studies have shown that sporadic FSGS can arise owing to mutations in podocin.36.Tsukaguchi H. Sudhakar A. Le T.C. et al.NPHS2 mutations in late-onset focal segmental glomerulosclerosis. R229Q is a common disease-associated allele.J Clin Invest. 2002; 110: 1659-1666Crossref PubMed Scopus (0) Google Scholar This leads one to ask if these patients have a ‘two-hit’ injury, that is, a gene mutation that by itself may not be sufficient to cause proteinuria, but in the presence of a second injury, such as hypertension or hypercholesterolemia, podocyte injury ensues. Although serological and other laboratory tests are informative in glomerular diseases, the definitive diagnosis in most nephrotic syndromes is a renal biopsy. However, the range of abnormalities seen on pathological examination of the renal biopsy can be highly variable in diseases of podocytes. At one extreme, despite massive proteinuria, light microscopy can be normal, such as minimal change disease. The other extreme is exemplified by classic or cellular FSGS, where glomerulosclerosis and glomerular tuft collapse are marked on light microscopy, with or without changes in podocyte number (increase or decrease). Regardless of the cause of podocyte damage, typical podocyte abnormalities are best seen on electron microscopy and include vacuolization, microcystic, or pseudocystic changes, the presence of cytoplasmic inclusion bodies, and detachment from the GBM. In areas of reduced podocyte number, there may be focal areas of denudation of the underlying GBM. Although these changes are common, the characteristic response to podocyte damage/injury is a change in shape called effacement, and this will be discussed in detail below. It should be noted that these electron microscopy changes do not typically distinguish one podocyte disease from another, but rather represent a common final pathway of the podocyte's response to injury. The clinical signature of podocyte damage is proteinuria, and in many instances, reduced renal function. The level of proteinuria can range from mild ( 3 g/day). The author will now focus the discussion on the mechanisms underlying proteinuria in response to podocyte injury (see Figure 1, Tables 2 and 3).Table 2Mechanisms leading to proteinuria following podocyte injuryCause of proteinuria following podocyte injurySpecific podocyte defectSlit diaphragm proteinsNephrin mutation in manPodocin mutation in manCD2AP haploinsufficiency in manFAT-1-targeted deletion in miceNeph-1-targeted deletion in miceReduced podocyte numberDetachmentApoptosisLack of adequate proliferationDNA damageHypertrophyPodocyte effacementChanges in slit diaphragm proteinsAbnormal podocyte–GBM interaction (α,β dystroglycans, α3β1 integrin)Actin cytoskeleton reorganization owing to synaptopodin, α-actinin-4, CDK5Loss of negative chargeInjury to apical membrane proteins (podocalyxin, NHERF2, Ezrin)Loss of podocyte anion charge↓Podocalyxin↓GLEPPAbnormal GBMProteases from podocyteOxidants from podocyteGBM thickening owing to matrix accumulation from podocyte↓Heparan sulfate proteoglycanGlomerular endothelial cell dysfunction↓VEGF from podocyteCDK, cyclin-dependent kinase; GBM, glomerular basement membrane; GLEPP, glomerular epithelial protein; NHERF, Na+/H+-exchanger regulatory factor; VEGF, vascular endothelial growth factor. Open table in a new tab Table 3Mediators and effects following podocyte injuryMediator from podocyteEffectReactive oxygen speciesCreation of holes in GBMPodocyte apoptosisPodocyte DNA damageEffacementLipid peroxidationProtein peroxidationAngiotensin IIPodocyte apoptosisPodocyte hypertrophyIncreases TGF-β levels → matrix accumulationIncreases VEGF levels → matrix accumulationReduces nephrin levelsIncreases p27 levelsIncreases IP-8 and IP-10 levelsMetalloproteinasesAlteration in GBM matrixDisruption of nephrin–NEPH2 complexProstaglandinsEndoplasmic reticulum stressMechanical stretchPodocyte detachmentPodocyte apoptosisInhibition of podocyte proliferationPodocyte hypertrophyTGF-βIncrease in matrix proteins leading to GBM thickeningPodocyte apoptosisIncreases metalloproteinasesSPARCPodocyte detachmentcAMP?Narrowing of filtration slits?Podocyte relaxationVEGF↑TGF-β levels↑Production of α3(IV) collagen by podocytesSignaling pathwaysERK, JNK, SAPKERK, extracellular signal-regulated kinase; GBM, glomerular basement membrane; JNK, c-Jun NH2-terminal kinase; NEPH, nephrin-neutral endopeptidase; SAPK, signal-activated protein kinase; SPARC, secreted protein acid rich in cysteine; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor. Open table in a new tab CDK, cyclin-dependent kinase; GBM, glomerular basement membrane; GLEPP, glomerular epithelial protein; NHERF, Na+/H+-exchanger regulatory factor; VEGF, vascular endothelial growth factor. ERK, extracellular signal-regulated kinase; GBM, glomerular basement membrane; JNK, c-Jun NH2-terminal kinase; NEPH, nephrin-neutral endopeptidase; SAPK, signal-activated protein kinase; SPARC, secreted protein acid rich in cysteine; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor. In 1957, Farquhar et al.37.Farquhar M.G. Vernier R.L. Good R.A. An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus.J Exp Med. 1957; 106: 649-660Crossref PubMed Google Scholar was the first to describe extensive foot process effacement in biopsies of patients with nephritic syndrome. Most authorities believe that effacement, also often referred to as fusion, retraction, or simplification, is a stereotypical reaction of podocytes to injury or damage. Scanning electron microscopy has shown that the change in podocyte shape called effacement consists of gradual simplification of the inter-digitating foot process pattern, resulting in the formation of a cell that looks flat and elongated. This is not fusion of neighboring cells. Rather, it is owing to retraction, widening, and shortening of the processes of each podocyte. The frequency of filtration slits is reduced,38.Drumond M.C. Kristal B. Myers B.D. et al.Structural basis for reduced glomerular filtration capacity in nephrotic humans.J Clin Invest. 1994; 94: 1187-1195Crossref PubMed Google Scholar giving the appearance of a continuous cytoplasmic sheet covering the GBM. Effacement is not specific to one disease, but rather is synonymous with podocyte injury of many forms. Animal models showed that effacement starts as a decrease in the degree of interdigitation by shortening and widening of foot processes. This is accompanied by degradation of some foot processes, followed by loss of the inter-digitating foot process pattern between individual cells. Foot process length decreases up to 70%, and the width increases up to 60% compared to normal. The resultant abnormal cell shape comprising a flattened and spread out cell is what we know as effacement. Studies have shown that effacement is not simply a passive phenomenon, but rather is an active process that is energy dependent, and is initiated by changes in the podocyte's cytoskeleton. The author does not know the answer to this seemingly easy question, and believes that there may be three views, and that the truth lies somewhere in between these. The first view is that effacement itself is sufficient to cause proteinuria. There are numerous examples where podocyte effacement is accompanied by proteinuria in experimental models and human disease. Indeed, one is usually hard pressed to find marked proteinuria without effacement in human disease. Data shows that indeed effacement precedes proteinuria in experimental models such as puromycin aminonucleoside nephrosis.39.Inokuchi S. Shirato I. Kobayashi N. et al.Re-evaluation of foot process effacement in acute puromycin aminonucleoside nephrosis.Kidney Int. 1996; 50: 1278-1287Abstract Full Text PDF PubMed Google Scholar Effacement results in a decrease in the filtration slit frequency along the GBM and has been associated with narrowing of the filtration slits and development of actual tight junctions between foot processes.40.Shirato I. Podocyte process effacement in vivo.Microsc Res Technol. 2002; 57: 241-246Crossref PubMed Scopus (0) Google Scholar Effacement also causes apical displacement of the slit diaphragm. These data, while association only, lead one to speculate that on
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