Proteinuria: an enzymatic disease of the podocyte?
2009; Elsevier BV; Volume: 77; Issue: 7 Linguagem: Inglês
10.1038/ki.2009.424
ISSN1523-1755
Autores Tópico(s)Lysosomal Storage Disorders Research
ResumoProteinuria is a major health-care problem that affects several hundred million people worldwide. Proteinuria is a cardinal sign and a prognostic marker of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Microalbuminuria is the earliest cue of renal complications of diabetes, obesity, and the metabolic syndrome. It can often progress to overt proteinuria that in 10–50% of patients is associated with the development of chronic kidney disease, ultimately requiring dialysis or transplantation. Therefore, reduction or prevention of proteinuria is highly desirable. Here we review recent novel insights into the pathogenesis and treatment of proteinuria, with a special emphasis on the emerging concept that proteinuria can result from enzymatic cleavage of essential regulators of podocyte actin dynamics by cytosolic cathepsin L (CatL), resulting in a motile podocyte phenotype. Finally, we describe signaling pathways controlling the podocyte actin cytoskeleton and motility and how these pathways can be manipulated for therapeutic benefit. Proteinuria is a major health-care problem that affects several hundred million people worldwide. Proteinuria is a cardinal sign and a prognostic marker of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Microalbuminuria is the earliest cue of renal complications of diabetes, obesity, and the metabolic syndrome. It can often progress to overt proteinuria that in 10–50% of patients is associated with the development of chronic kidney disease, ultimately requiring dialysis or transplantation. Therefore, reduction or prevention of proteinuria is highly desirable. Here we review recent novel insights into the pathogenesis and treatment of proteinuria, with a special emphasis on the emerging concept that proteinuria can result from enzymatic cleavage of essential regulators of podocyte actin dynamics by cytosolic cathepsin L (CatL), resulting in a motile podocyte phenotype. Finally, we describe signaling pathways controlling the podocyte actin cytoskeleton and motility and how these pathways can be manipulated for therapeutic benefit. In a healthy person, urinary protein excretion is less than 150 mg/day and consists mainly of filtered plasma proteins (60%) and tubular Tamm-Horsfall proteins (40%). The main plasma protein in the urine is albumin, constituting about 20% of daily protein excretion. In healthy subjects, the daily amount of urinary albumin is less than 20 mg (13.8 mg/min).1.Orth S.R. Ritz E. The nephrotic syndrome.N Engl J Med. 1998; 338: 1202-1211Crossref PubMed Scopus (242) Google Scholar Proteinuria usually reflects an increase in glomerular permeability for albumin and other plasma macromolecules.1.Orth S.R. Ritz E. The nephrotic syndrome.N Engl J Med. 1998; 338: 1202-1211Crossref PubMed Scopus (242) Google Scholar A 24-h urine collection containing more than 150 mg of protein is considered pathological. There are several basic types of proteinuria; for example, glomerular, tubular, overflow, and exercise-induced (Table 1). Glomerular proteinuria is the most common form (around 90%). Low molecular weight molecules, such as β2-microglobulin, amino acids, and immunoglobulin light chains, have a molecular weight of about 25 kDa (albumin is 69 kDa). These smaller proteins are readily filtered across the glomerular filtration barrier and then fully reabsorbed by the proximal tubule. A variety of diseases that affect tubular and interstitial cell integrity impair the tubular reabsorption of these molecules.2.Bergon E. Granados R. Fernandez-Segoviano P. et al.Classification of renal proteinuria: a simple algorithm.Clin Chem Lab Med. 2002; 40: 1143-1150Crossref PubMed Google Scholar Some forms of glomerular diseases are also accompanied by tubular injury and tubular proteinuria.3.de Zeeuw D. Lewis E.J. Remuzzi G. et al.Renoprotective effects of renin-angiotensin-system inhibitors.Lancet. 2006; 367 (author reply 900-892): 899-900Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Pathological processes, such as multiple myeloma with a production of paraproteins, can result in increased excretion of low molecular weight proteins into the urine, a process termed overflow proteinuria. In this scenario, proteinuria results from the amount of filtered proteins exceeding the reabsorptive capacity of the proximal tubule.4.Carroll M.F. Temte J.L. Proteinuria in adults: a diagnostic approach.Am Fam Physician. 2000; 62: 1333-1340PubMed Google Scholar Dynamic exercise can also result in increased urinary excretion of proteins, predominantly of plasma origin, during and following physical exercise. A number of terms have been used to describe this phenomenon—post-exercise proteinuria, athletic pseudonephritis, exercise proteinuria, or exercise-induced proteinuria.5.Bellinghieri G. Savica V. Santoro D. Renal alterations during exercise.J Ren Nutr. 2008; 18: 158-164Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Maximal rates of proteinuria occur approximately 30 min after exercise, with a resolution toward resting levels within 24–48 h. The magnitude of proteinuria varies from near normal to heavy (>7 g/day), with the greatest levels up to 100 times that of rest observed after high-intensity exercise, such as a marathon. It is noteworthy that post-exercise proteinuria is transient in nature and not associated with any particular renal disease, raising the intriguing possibility that at least some forms of proteinuria (e.g., post-exercise, post-prandial, infection-associated) may reflect a normal, physiological response of the human body (Table 1). In this review, we focus on the emerging concept that proteinuria can result from enzymatic cleavage of essential regulators of podocyte actin dynamics by cytosolic cathepsin L (CatL). Because of space limitations, genetic6.Tryggvason K. Patrakka J. Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria.N Engl J Med. 2006; 354: 1387-1401Crossref PubMed Scopus (310) Google Scholar and other causes of proteinuria7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar will not be discussed in detail.Table 1Types of proteinuriaTypesCharacteristicsGlomerularMost common form, up to 90%Feature of chronic kidney diseaseLoss of albumin and higher molecular weight proteinsTubularLow molecular weight proteins, such as β2-microglobulinOverflowIncreased production, that is, light chains in multiple myelomaPost-exerciseTransient benignCan be up to 10 g/dayPost-prandialTransient physiological proteinuriaPossibly through insulin action in podocytesInfection-Physiological responseassociatedMediated by toll-receptorsPossibly involved in clearing pathogens from the circulation Open table in a new tab The kidney glomerulus (Figure 1a) is a highly specialized vascular bed that ensures the selective ultrafiltration of plasma so that the essential proteins are retained in the blood.8.Somlo S. Mundel P. Getting a foothold in nephrotic syndrome.Nat Genet. 2000; 24: 333-335Crossref PubMed Scopus (184) Google Scholar, 9.Farquhar M.G. The primary glomerular filtration barrier—basement membrane or epithelial slits?.Kidney Int. 1975; 8: 197-211Abstract Full Text PDF PubMed Google Scholar, 10.Mundel P. Kriz W. Structure and function of podocytes: an update.Anat Embryol (Berl). 1995; 192: 385-397Crossref PubMed Scopus (198) Google Scholar The glomerular basement membrane (GBM) provides the primary structural support for the glomerular tuft. The basic unit of the glomerular tuft is a single capillary. The fenestrated glomerular endothelial cells and mesangial cells are located inside the GBM, whereas podocytes are attached to the outer aspect of the GBM (Figure 1a). The glomerular capillaries function as the filtration barrier.9.Farquhar M.G. The primary glomerular filtration barrier—basement membrane or epithelial slits?.Kidney Int. 1975; 8: 197-211Abstract Full Text PDF PubMed Google Scholar,11.Farquhar M.G. The glomerular basement membrane: not gone, just forgotten.J Clin Invest. 2006; 116: 2090-2093Crossref PubMed Scopus (39) Google Scholar The filtration barrier is characterized by distinct charge and size selectivity, thereby ensuring that albumin and other plasma proteins are retained in the circulation.9.Farquhar M.G. The primary glomerular filtration barrier—basement membrane or epithelial slits?.Kidney Int. 1975; 8: 197-211Abstract Full Text PDF PubMed Google Scholar,11.Farquhar M.G. The glomerular basement membrane: not gone, just forgotten.J Clin Invest. 2006; 116: 2090-2093Crossref PubMed Scopus (39) Google Scholar Proteinuria occurs when the permeability of the glomerular barrier is increased.11.Farquhar M.G. The glomerular basement membrane: not gone, just forgotten.J Clin Invest. 2006; 116: 2090-2093Crossref PubMed Scopus (39) Google Scholar Direct proof for this concept came from human monogenetic studies showing that mutations affecting podocyte proteins, including α-actinin-4,12.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 CD2AP,13.Lowik M.M. Groenen P.J. Pronk I. et al.Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation.Kidney Int. 2007; 72: 1198-1203Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar nephrin,14.Kestila M. Lenkkeri 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 PLCE1,15.Hinkes B. Wiggins R.C. Gbadegesin R. et al.Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.Nat Genet. 2006; 38: 1397-1405Crossref PubMed Scopus (274) Google Scholar podocin,16.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: 349-354Crossref PubMed Scopus (870) Google Scholar and TRPC6,17.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,18.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 lead to renal disease owing to disruption of the filtration barrier and rearrangement of the podocyte actin cytoskeleton.6.Tryggvason K. Patrakka J. Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria.N Engl J Med. 2006; 354: 1387-1401Crossref PubMed Scopus (310) Google Scholar,7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar Additional proteins regulating the podocyte actin cytoskeleton, such as Rho GDIa,19.Togawa A. Miyoshi J. Ishizaki H. et al.Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.Oncogene. 1999; 18: 5373-5380Crossref PubMed Scopus (150) Google Scholar,20.Shibata S. Nagase M. Yoshida S. et al.Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease.Nat Med. 2008; 14: 1370-1376Crossref PubMed Scopus (201) Google Scholar podocalyxin,21.Schmieder S. Nagai M. Orlando R.A. et al.Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells.J Am Soc Nephrol. 2004; 15: 2289-2298Crossref PubMed Scopus (71) Google Scholar FAT1,22.Moeller M.J. Soofi A. Braun G.S. et al.Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization.EMBO J. 2004; 23: 3769-3779Crossref PubMed Scopus (103) Google Scholar Nck1/223.Jones N. Blasutig I.M. Eremina V. et al.Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes.Nature. 2006; 440: 818-823Crossref PubMed Scopus (253) Google Scholar,24.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: 1346-1359Crossref PubMed Scopus (196) Google Scholar and synaptopodin,25.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: 1188-1198Crossref PubMed Scopus (169) Google Scholar,26.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: 485-491Crossref PubMed Google Scholar are also of critical importance for sustained function of the glomerular filtration barrier.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar Some years ago, using two-photon microscopy, Russo et al.27.Russo L.M. Sandoval R.M. McKee M. et al.The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: Retrieval is disrupted in nephrotic states.Kidney Int. 2007; 71: 504-513Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar claimed that the normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells. However, several recent studies convincingly refuted this alternative concept of a ‘leaky’ glomerular barrier.28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar, 29.Tanner G.A. Rippe C. Shao Y. et al.Glomerular permeability to macromolecules in the Necturus kidney.Am J Physiol Renal Physiol. 2009; 296: F1269-F1278Crossref PubMed Scopus (0) Google Scholar, 30.Peti-Peterdi J. Independent two-photon measurements of albumin GSC give low values.Am J Physiol Renal Physiol. 2009; 296: F1255-F1257Crossref PubMed Scopus (38) Google Scholar Using two-photon microscopy as well, Tanner28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar and Peti-Peterdi30.Peti-Peterdi J. Independent two-photon measurements of albumin GSC give low values.Am J Physiol Renal Physiol. 2009; 296: F1255-F1257Crossref PubMed Scopus (38) Google Scholar independently and directly confirmed the classical view that the glomerular filter is the primary barrier for albumin and that the glomerular sieving coefficient for albumin is extremely low.28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar, 29.Tanner G.A. Rippe C. Shao Y. et al.Glomerular permeability to macromolecules in the Necturus kidney.Am J Physiol Renal Physiol. 2009; 296: F1269-F1278Crossref PubMed Scopus (0) Google Scholar, 30.Peti-Peterdi J. Independent two-photon measurements of albumin GSC give low values.Am J Physiol Renal Physiol. 2009; 296: F1255-F1257Crossref PubMed Scopus (38) Google Scholar The values determined by Tanner28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar and Peti-Peterdi30.Peti-Peterdi J. Independent two-photon measurements of albumin GSC give low values.Am J Physiol Renal Physiol. 2009; 296: F1255-F1257Crossref PubMed Scopus (38) Google Scholar are somewhat higher than most values determined by kidney micropuncture, but they are still an order of magnitude less than the values reported by Russo et al.27.Russo L.M. Sandoval R.M. McKee M. et al.The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: Retrieval is disrupted in nephrotic states.Kidney Int. 2007; 71: 504-513Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Tanner28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar and Peti-Peterdi30.Peti-Peterdi J. Independent two-photon measurements of albumin GSC give low values.Am J Physiol Renal Physiol. 2009; 296: F1255-F1257Crossref PubMed Scopus (38) Google Scholar also demonstrated how the abnormally high glomerular sieving coefficient postulated by Russo et al. most likely resulted from technical limitations of the experimental approach.28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar,30.Peti-Peterdi J. Independent two-photon measurements of albumin GSC give low values.Am J Physiol Renal Physiol. 2009; 296: F1255-F1257Crossref PubMed Scopus (38) Google Scholar In conclusion, the classic view of a highly size- and charge-selective glomerular barrier still holds.28.Tanner G.A. Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study.Am J Physiol Renal Physiol. 2009; 296: F1258-F1265Crossref PubMed Scopus (50) Google Scholar, 31.Haraldsson B. Jeansson M. Glomerular filtration barrier.Curr Opin Nephrol Hypertens. 2009; 18: 331-335Crossref PubMed Scopus (39) Google Scholar, 32.Haraldsson B. Nystrom J. Deen W.M. Properties of the glomerular barrier and mechanisms of proteinuria.Physiol Rev. 2008; 88: 451-487Crossref PubMed Scopus (296) Google Scholar, 33.Navar L.G. Glomerular permeability: a never-ending saga.Am J Physiol Renal Physiol. 2009; 296: F1266-F1268Crossref PubMed Scopus (10) Google Scholar Differentiated podocytes are mesenchymal-like cells that arise from epithelial precursors during renal development.34.Reeves W. Caulfield J.P. Farquhar M.G. Differentiation of epithelial foot processes and filtration slits: sequential appearance of occluding junctions, epithelial polyanion, and slit membranes in developing glomeruli.Lab Invest. 1978; 39: 90-100PubMed Google Scholar Similar to pericytes, podocytes never embrace a capillary in total.10.Mundel P. Kriz W. Structure and function of podocytes: an update.Anat Embryol (Berl). 1995; 192: 385-397Crossref PubMed Scopus (198) Google Scholar Podocytes consist of three morphologically and functionally different segments: a cell body, major processes, and foot processes (FPs).10.Mundel P. Kriz W. Structure and function of podocytes: an update.Anat Embryol (Berl). 1995; 192: 385-397Crossref PubMed Scopus (198) Google Scholar From the cell body, major processes arise that split into FP (Figure 1a). FPs contain an actin-based cytoskeleton that is linked to the GBM.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar Podocyte FPs form a highly branched interdigitating network with FPs of neighboring podocytes connected by the slit diaphragm (SD) (Figure 1a). The SD is a modified adherens junction35.Reiser J. Kriz W. Kretzler M. et al.The glomerular slit diaphragm is a modified adherens junction.J Am Soc Nephrol. 2000; 11: 1-8Crossref PubMed Google Scholar that covers the 30–50 nm wide filtration slits (Figure 1a), thereby establishing the final barrier to urinary protein loss.8.Somlo S. Mundel P. Getting a foothold in nephrotic syndrome.Nat Genet. 2000; 24: 333-335Crossref PubMed Scopus (184) Google Scholar The extracellular portion of the SD is made up of rod-like units that are connected in the center to a linear bar, forming a zipper-like pattern, with pores about the same size as or smaller than albumin.10.Mundel P. Kriz W. Structure and function of podocytes: an update.Anat Embryol (Berl). 1995; 192: 385-397Crossref PubMed Scopus (198) Google Scholar The function of podocytes is largely based on their complex cell architecture, in particular on the maintenance of the normal FP structure with their highly ordered parallel contractile actin filament bundles7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar,36.Drenckhahn D. Franke R.P. Ultrastructural organization of contractile and cytoskeletal proteins in glomerular podocytes of chicken, rat, and man.Lab Invest. 1988; 59: 673-682PubMed Google Scholar (Figure 1a). FPs are functionally defined by three membrane domains: the apical membrane domain, the SD, and the basal membrane domain or sole plate that is associated with the GBM.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar,37.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 All three domains are physically and functionally linked to the FP actin cytoskeleton. Proteins regulating the plasticity of the podocyte actin cytoskeleton are therefore of critical importance for sustained function of the glomerular filter.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar At the SD, multiple membrane proteins are present that are connected to the actin cytoskeleton through a variety of adaptor and effector proteins that may function as a key sensor and regulator of the permanent changes in FP shape and length.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar Changes in podocyte FP dynamics need to be precisely coordinated with FPs of neighboring podocytes, thereby preserving the integrity of the filtration barrier during FP movements, with functional coupling of opposing FPs and signaling cascades on both sides of the SD.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar Mutations in the NPHS1 gene encoding for the SD protein nephrin have been identified as the cause of congenital nephrotic syndrome of the Finnish type.14.Kestila M. Lenkkeri 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 It is noteworthy that nephrin is connected to the actin cytoskeleton through several adapter proteins and has a pivotal part in the regulation of podocyte actin dynamics.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar,38.Tryggvason K. Pikkarainen T. Patrakka J. Nck links nephrin to actin in kidney podocytes.Cell. 2006; 125: 221-224Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Among others (reviewed in detail by Faul et al.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar), a recently discovered signaling pathway couples nephrin to the actin cytoskeleton through the adaptor protein Nck.23.Jones N. Blasutig I.M. Eremina V. et al.Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes.Nature. 2006; 440: 818-823Crossref PubMed Scopus (253) Google Scholar,24.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: 1346-1359Crossref PubMed Scopus (196) Google Scholar After nephrin phosphorylation by Fyn,39.Verma R. Wharram B. Kovari I. et al.Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin.J Biol Chem. 2003; 278: 20716-20723Crossref PubMed Scopus (141) Google Scholar Nck binds to phospho-nephrin and Nck binds to N-WASP.23.Jones N. Blasutig I.M. Eremina V. et al.Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes.Nature. 2006; 440: 818-823Crossref PubMed Scopus (253) Google Scholar,24.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: 1346-1359Crossref PubMed Scopus (196) Google Scholar This in turn leads to the activation of the Arp2/3 complex, a major regulator of actin dynamics.7.Faul C. Asanuma K. Yanagida-Asanuma E. et al.Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton.Trends Cell Biol. 2007; 17: 428-437Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 23.Jones N. Blasutig I.M. Eremina V. et al.Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes.Nature. 2006; 440: 818-823Crossref PubMed Scopus (253) Google Scholar, 24.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: 1346-1359Crossref PubMed Scopus (196) Google Scholar, 38.Tryggvason K. Pikkarainen T. Patrakka J. Nck links nephrin to actin in kidney podocytes.Cell. 2006; 125: 221-224Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Podocytes can be injured in many forms of human and experimental glomerular disease, including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous glomerulopathy, diabetic nephropathy, and lupus nephritis.8.Somlo S. Mundel P. Getting a foothold in nephrotic syndrome.Nat Genet. 2000; 24: 333-335Crossref PubMed Scopus (184) Google Scholar,37.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 Characteristic changes are actin cytoskeleton reorganization of the involved FP, which typically leads to FP effacement and SD disruption12.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,40.Tryggvason K. Wartiovaara J. Molecular basis of glomerular permselectivity.Curr Opin Nephrol Hypertens. 2001; 10: 543-549Crossref PubMed Scopus (163) Google Scholar (Figure 1b). Interference with any of the three FP domains changes the actin cytoskeleton from parallel contractile bundles36.Drenckhahn D. Franke R.P. Ultrastructural organization of contractile and cytoskeletal proteins in glomerular podocytes of chicken, rat, and man.Lab Invest. 1988; 59: 673-682PubMed Google Scholar into a dense network with FP effacement (reflected by the simplification of the FP structure and loss of the normal interdigitating pattern) (Figure 1b) and proteinuria.37.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 Causes of FP effacement and proteinuria include the following: (i) changes in SD structure or function,39.Verma R. Wharram B. Kovari I. et al.Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin.J Biol Chem. 2003; 278: 20716-20723Crossref PubMed Scopus (141) Google Scholar, 41.Simons M. Schwarz K. Kriz W. et al.Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm.Am J Pathol. 2001; 159: 1069-1077Abstract Full Text Full Text PDF PubMed Google Scholar, 42.Wei C. Moller C.C. Altintas M.M. et al.Modification of kidney barrier function by the urokinase receptor.Nat Med. 2008; 14: 55-63Crossref PubMed Scopus (211) Google Scholar (ii) interference with the GBM or the podocyte–GBM interaction,43.Regele H.M. 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: 403-412Crossref PubMed Google Scholar, 44.Raats C.J. Bakker M.A. van den Born J. et al.Hydroxyl radicals depolymerize glomerular heparan sulfate in vitro and in experimental nephrotic syndrome.J Biol Chem. 1997; 272: 26734-26741Crossref PubMed Scopus (85) Google Schol
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