Pediatric Nephrology

, Volume 19, Issue 2, pp 130–137

Dynamic (re)organization of the podocyte actin cytoskeleton in the nephrotic syndrome



The visceral glomerular epithelial cell, also known as the podocyte, plays an important role in the maintenance of renal glomerular function. This cell type is highly specialized and its foot processes together with the interposed slit diaphragm (SD) form the final barrier to urinary protein loss. Effacement of foot processes is associated with the development of proteinuria and—if not reversed in a certain time—with permanent deterioration of the glomerular filter. To maintain an intact glomerular filter barrier, podocyte-podocyte interactions and podocyte interactions with the glomerular basement membrane (GBM) are essential. Recent years have highlighted podocyte functions by unraveling the molecular composition of the SD, but have also clarified the important role of the podocyte actin cytoskeleton, and the podocyte-GBM interaction in the development of foot process (FP) effacement. This review provides an update of podocyte functions with respect to novel podocyte-specific proteins and also focuses on the dynamic interaction between the actin cytoskeleton of podocytes, their cell surface receptors and the GBM.


Podocytes Foot process effacement Proteinuria Integrins Glomerular basement membrane Dystroglycan 


  1. 1.
    Somlo S, Mundel P (2000) Getting a foothold in nephrotic syndrome. Nat Genet 24:333–335CrossRefPubMedGoogle Scholar
  2. 2.
    Kerjaschki D (2001) Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 108:1583–1587CrossRefPubMedGoogle Scholar
  3. 3.
    Tryggvason K, Wartiovaara J (2001) Molecular basis of glomerular permselectivity. Curr Opin Nephrol Hypertens 10:543–549Google Scholar
  4. 4.
    Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR (2000) Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24:251–256CrossRefPubMedGoogle Scholar
  5. 5.
    Mundel P, Shankland SJ (2002) Podocyte biology and response to injury. J Am Soc Nephrol 13:3005–3015PubMedGoogle Scholar
  6. 6.
    Topham PS, Kawachi H, Haydar SA, Chugh S, Addona TA, Charron KB, Holzman LB, Shia M, Shimizu F, Salant DJ (1999) Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin. J Clin Invest 104:1559–1566PubMedGoogle Scholar
  7. 7.
    Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS (2003) Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest 112:209–221CrossRefPubMedGoogle Scholar
  8. 8.
    Simons M, Schwarz K, Kriz W, Miettinen A, Reiser J, Mundel P, Holthofer H (2001) Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. Am J Pathol 159:1069–1077Google Scholar
  9. 9.
    Verma R, Wharram B, Kovari I, Kunkel R, Nihalani D, Wary KK, Wiggins RC, Killen P, Holzman LB (2003) Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin. J Biol Chem 278:20716–20723CrossRefPubMedGoogle Scholar
  10. 10.
    Regele HM, Fillipovic E, Langer B, Poczewki H, Kraxberger I, Bittner RE, Kerjaschki D (2000) Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis. J Am Soc Nephrol 11:403–412PubMedGoogle Scholar
  11. 11.
    Raats CJ, Bakker MA, van den Born J, Berden JH (1997) Hydroxyl radicals depolymerize glomerular heparan sulfate in vitro and in experimental nephrotic syndrome. J Biol Chem 272:26734–26741CrossRefPubMedGoogle Scholar
  12. 12.
    Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, Jaenisch R (1996) Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122:3537–3547PubMedGoogle Scholar
  13. 13.
    Noakes PG, Miner JH, Gautam M, Cunningham JM, Sanes JR, Merlie JP (1995) The renal glomerulus of mice lacking s-laminin/laminin beta 2: nephrosis despite molecular compensation by laminin beta 1. Nat Genet 10:400–406PubMedGoogle Scholar
  14. 14.
    Miner JH, Lewis RM, Sanes JR (1995) Molecular cloning of a novel laminin chain, alpha 5, and widespread expression in adult mouse tissues. J Biol Chem 270:28523–28526CrossRefPubMedGoogle Scholar
  15. 15.
    Kretzler M, Teixeira VP, Unschuld PG, Cohen CD, Wanke R, Edenhofer I, Mundel P, Schlondorff D, Holthofer H (2001) Integrin-linked kinase as a candidate downstream effector in proteinuria. FASEB J 15:1843–1845PubMedGoogle Scholar
  16. 16.
    Smoyer WE, Mundel P (1998) Regulation of podocyte structure during the development of nephrotic syndrome. J Mol Med 76:172–183CrossRefPubMedGoogle Scholar
  17. 17.
    Kos CH, Le TC, Sinha S, Henderson JM, Kim SH, Sugimoto H, Kalluri R, Gerszten RE, Pollak MR (2003) Mice deficient in alpha-actinin-4 have severe glomerular disease. J Clin Invest 111:1683–1690CrossRefPubMedGoogle Scholar
  18. 18.
    Orlando RA, Takeda T, Zak B, Schmieder S, Benoit VM, McQuistan T, Furthmayr H, Farquhar MG (2001) The glomerular epithelial cell anti-adhesin podocalyxin associates with the actin cytoskeleton through interactions with ezrin. J Am Soc Nephrol 12:1589–1598PubMedGoogle Scholar
  19. 19.
    Takeda T, McQuistan T, Orlando RA, Farquhar MG (2001) Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton. J Clin Invest 108:289–301CrossRefPubMedGoogle Scholar
  20. 20.
    Quaggin SE (2002) Transcriptional regulation of podocyte specification and differentiation. Microsc Res Tech 57:208–211CrossRefPubMedGoogle Scholar
  21. 21.
    Dressler GR, Woolf AS (1999) Pax2 in development and renal disease. Int J Dev Biol 43:463–468PubMedGoogle Scholar
  22. 22.
    Stayner CK, Cunliffe HE, Ward TA, Eccles MR (1998) Cloning and characterization of the human PAX2 promoter. J Biol Chem 273:25472–25479CrossRefPubMedGoogle Scholar
  23. 23.
    Quaggin SE, Schwartz L, Cui S, Igarashi P, Deimling J, Post M, Rossant J (1999) The basic-helix-loop-helix protein Pod1 is critically important for kidney and lung organogenesis. Development 126:5771–5783PubMedGoogle Scholar
  24. 24.
    Lu J, Richardson JA, Olson EN (1998) Capsulin: a novel bHLH transcription factor expressed in epicardial progenitors and mesenchyme of visceral organs. Mech Dev 73:23–32PubMedGoogle Scholar
  25. 25.
    Imaki J, Onodera H, Tsuchiya K, Imaki T, Mochizuki T, Mishima T, Yamashita K, Yoshida K, Sakai M (2000) Developmental expression of maf-1 messenger ribonucleic acids in rat kidney by in situ hybridization histochemistry. Biochem Biophys Res Commun 272:777–782CrossRefPubMedGoogle Scholar
  26. 26.
    Sadl V, Jin F, Yu J, Cui S, Holmyard D, Quaggin S, Barsh G, Cordes S (2002) The mouse Kreisler (Krml1/MafB) segmentation gene is required for differentiation of glomerular visceral epithelial cells. Dev Biol 249:16–29CrossRefPubMedGoogle Scholar
  27. 27.
    Dreyer SD, Morello R, German MS, Zabel B, Winterpacht A, Lunstrum GP, Horton WA, Oberg KC, Lee B (2000) LMX1B transactivation and expression in nail-patella syndrome. Hum Mol Genet 9:1067–1074PubMedGoogle Scholar
  28. 28.
    Kume T, Deng K, Hogan BL (2000) Minimal phenotype of mice homozygous for a null mutation in the forkhead/winged helix gene, Mf2. Mol Cell Biol 20:1419–1425CrossRefPubMedGoogle Scholar
  29. 29.
    Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome PG-575-82. Mol Cell 1:575–582PubMedGoogle Scholar
  30. 30.
    Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestil M, Jalanko H, Holmberg C, Tryggvason K (1999) Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci U S A 96:7962–7967CrossRefPubMedGoogle Scholar
  31. 31.
    Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354CrossRefPubMedGoogle Scholar
  32. 32.
    Shih NY, Li J, Cotran R, Mundel P, Miner JH, Shaw AS (2001) CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. Am J Pathol 159:2303–2308Google Scholar
  33. 33.
    Kim JM, Wu H, Green G, Winkler CA, Kopp JB, Miner JH, Unanue ER, Shaw AS (2003) CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 300:1298–1300CrossRefPubMedGoogle Scholar
  34. 34.
    Ciani L, Patel A, Allen ND, Ffrench-Constant C (2003) Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol 23:3575–3582CrossRefPubMedGoogle Scholar
  35. 35.
    Hamano Y, Grunkemeyer JA, Sudhakar A, Zeisberg M, Cosgrove D, Morello R, Lee B, Sugimoto H, Kalluri R (2002) Determinants of vascular permeability in the kidney glomerulus. J Biol Chem 277:31154–31162CrossRefPubMedGoogle Scholar
  36. 36.
    Rantanen M, Palmen T, Patari A, Ahola H, Lehtonen S, Astrom E, Floss T, Vauti F, Wurst W, Ruiz P, Kerjaschki D, Holthofer H (2002) Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions. J Am Soc Nephrol 13:1586–1594PubMedGoogle Scholar
  37. 37.
    Lahdenpera J, Kilpelainen P, Liu XL, Pikkarainen T, Reponen P, Ruotsalainen V, Tryggvason K (2003) Clustering-induced tyrosine phosphorylation of nephrin by Src family kinases. Kidney Int 64:404–413CrossRefPubMedGoogle Scholar
  38. 38.
    Donoviel DB, Freed DD, Vogel H, Potter DG, Hawkins E, Barrish JP, Mathur BN, Turner CA, Geske R, Montgomery CA, Starbuck M, Brandt M, Gupta A, Ramirez-Solis R, Zambrowicz BP, Powell DR (2001) Proteinuria and perinatal lethality in mice lacking neph1, a novel protein with homology to nephrin. Mol Cell Biol 21:4829–4836CrossRefPubMedGoogle Scholar
  39. 39.
    Huber TB, Schmidts M, Gerke P, Schermer B, Zahn A, Hartleben B, Sellin L, Walz G, Benzing T (2003) The carboxy terminus of Neph family members binds to the PDZ domain protein Zonula occludens-1. J Biol Chem (in press)Google Scholar
  40. 40.
    Schnabel E, Anderson JM, Farquhar MG (1990) The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium. J Cell Biol 111:1255–1263PubMedGoogle Scholar
  41. 41.
    Li C, Ruotsalainen V, Tryggvason K, Shaw AS, Miner JH (2000) CD2AP is expressed with nephrin in developing podocytes and is found widely in mature kidney and elsewhere. Am J Physiol Renal Physiol 279:F785–792PubMedGoogle Scholar
  42. 42.
    Dustin ML, Olszowy MW, Holdorf AD, Li J, Bromley S, Desai N, Widder P, Rosenberger F, van der Merwe PA, Allen PM, Shaw AS (1998) A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94:667–677PubMedGoogle Scholar
  43. 43.
    Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P (2001) Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 108:1621–1629CrossRefPubMedGoogle Scholar
  44. 44.
    Lynch DK, Winata SC, Lyons RJ, Hughes WE, Lehrbach GM, Wasinger V, Corthals G, Cordwell S, Daly RJ (2003) A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. J Biol Chem 278:21805–21813CrossRefPubMedGoogle Scholar
  45. 45.
    Cormont M, Meton I, Mari M, Monzo P, Keslair F, Gaskin C, McGraw TE, Le Marchand-Brustel Y (2003) CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl. Traffic 4:97–112CrossRefPubMedGoogle Scholar
  46. 46.
    Inoue T, Yaoita E, Kurihara H, Shimizu F, Sakai T, Kobayashi T, Ohshiro K, Kawachi H, Okada H, Suzuki H, Kihara I, Yamamoto T (2001) FAT is a component of glomerular slit diaphragms. Kidney Int 59:1003–1012CrossRefPubMedGoogle Scholar
  47. 47.
    Cho EA, Patterson LT, Brookhiser WT, Mah S, Kintner C, Dressler GR (1998) Differential expression and function of cadherin-6 during renal epithelium development. Development 125:803–812PubMedGoogle Scholar
  48. 48.
    Reiser J, Kriz W, Kretzler M, Mundel P (2000) The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol 11:1–8PubMedGoogle Scholar
  49. 49.
    Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attie T, Gubler MC, Antignac C (2002) Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 160:131–139PubMedGoogle Scholar
  50. 50.
    Sellin L, Huber TB, Gerke P, Quack I, Pavenstadt H, Walz G (2003) NEPH1 defines a novel family of podocin interacting proteins. FASEB J 17:115–117PubMedGoogle Scholar
  51. 51.
    Adler S (1992) Characterization of glomerular epithelial cell matrix receptors. Am J Pathol 141:571–578PubMedGoogle Scholar
  52. 52.
    Raats CJ, van Den Born J, Bakker MA, Oppers-Walgreen B, Pisa BJ, Dijkman HB, Assmann KJ, Berden JH (2000) Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies. Am J Pathol 156:1749–1765PubMedGoogle Scholar
  53. 53.
    Suzuki A, Yoshida M, Hayashi K, Mizuno Y, Hagiwara Y, Ozawa E (1994) Molecular organization at the glycoprotein-complex-binding site of dystrophin. Three dystrophin-associated proteins bind directly to the carboxy-terminal portion of dystrophin. Eur J Biochem 220:283–292PubMedGoogle Scholar
  54. 54.
    Chen YJ, Spence HJ, Cameron JM, Jess T, Ilsley JL, Winder SJ (2003) Direct interaction of beta-dystroglycan with F-actin. Biochem J (in press)Google Scholar
  55. 55.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687PubMedGoogle Scholar
  56. 56.
    Hemler ME (1998) Integrin associated proteins. Curr Opin Cell Biol 10:578–585CrossRefPubMedGoogle Scholar
  57. 57.
    Kreidberg JA (2000) Functions of alpha3beta1 integrin. Curr Opin Cell Biol 12:548–553CrossRefPubMedGoogle Scholar
  58. 58.
    Chen HC, Chen CA, Guh JY, Chang JM, Shin SJ, Lai YH (2000) Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci 67:2345–2353CrossRefPubMedGoogle Scholar
  59. 59.
    Regoli M, Bendayan M (1997) Alterations in the expression of the alpha 3 beta 1 integrin in certain membrane domains of the glomerular epithelial cells (podocytes) in diabetes mellitus. Diabetologia 40:15–22CrossRefPubMedGoogle Scholar
  60. 60.
    Baraldi A, Furci L, Zambruno G, Rubbiani E, Annessi G, Lusvarghi E (1992) Very late activation-3 integrin is the dominant beta 1-integrin on the glomerular capillary wall: an immunofluorescence study in nephrotic syndrome. Nephron 62:382–388PubMedGoogle Scholar
  61. 61.
    Kambham N, Tanji N, Seigle RL, Markowitz GS, Pulkkinen L, Uitto J, D’Agati VD (2000) Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis 36:190–196PubMedGoogle Scholar
  62. 62.
    Mayer G, Boileau G, Bendayan M (2003) Furin interacts with proMT1-MMP and integrin alphaV at specialized domains of renal cell plasma membrane. J Cell Sci 116:1763–1773CrossRefPubMedGoogle Scholar
  63. 63.
    Miner JH (2001) Mystery solved: discovery of a novel integrin ligand in the developing kidney. J Cell Biol 154:257–259CrossRefPubMedGoogle Scholar
  64. 64.
    Giancotti FG (2003) A structural view of integrin activation and signaling. Dev Cell 4:149–151PubMedGoogle Scholar
  65. 65.
    Ballestrem C, Hinz B, Imhof BA, Wehrle-Haller B (2001) Marching at the front and dragging behind: differential alphaVbeta3-integrin turnover regulates focal adhesion behavior. J Cell Biol 155:1319–1332CrossRefPubMedGoogle Scholar
  66. 66.
    Miner JH (1999) Renal basement membrane components. Kidney Int 56:2016–2024CrossRefPubMedGoogle Scholar
  67. 67.
    Abbi S, Guan JL (2002) Focal adhesion kinase: protein interactions and cellular functions. Histol Histopathol 17:1163–1171PubMedGoogle Scholar
  68. 68.
    Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635CrossRefPubMedGoogle Scholar
  69. 69.
    Chan YM, Bonnemann CG, Lidov HG, Kunkel LM (1998) Molecular organization of sarcoglycan complex in mouse myotubes in culture. J Cell Biol 143:2033–2044CrossRefPubMedGoogle Scholar
  70. 70.
    Hannigan GE, Leung Hagesteijn C, Fitz Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S (1996) Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 379:91–96PubMedGoogle Scholar
  71. 71.
    Shirato I, Sakai T, Kimura K, Tomino Y, Kriz W (1996) Cytoskeletal changes in podocytes associated with foot process effacement in Masugi nephritis. Am J Pathol 148:1283–1296PubMedGoogle Scholar
  72. 72.
    Seiler MW, Venkatachalam MA, Cotran RS (1975) Glomerular epithelium: structural alterations induced by polycations. Science 189:390–393PubMedGoogle Scholar
  73. 73.
    Smoyer WE, Ransom RF (2002) Hsp27 regulates podocyte cytoskeletal changes in an in vitro model of podocyte process retraction. FASEB J 16:315–326PubMedGoogle Scholar
  74. 74.
    Mundel P, Kriz W (1996) Cell culture of podocytes. Exp Nephrol 4:263–266PubMedGoogle Scholar
  75. 75.
    Mundel P, Gilbert P, Kriz W (1991) Podocytes in glomerulus of rat kidney express a characteristic 44 KD protein. J Histochem Cytochem 39:1047–1056PubMedGoogle Scholar
  76. 76.
    Kemeny E, Durmuller U, Nickeleit V, Gudat F, Mihatsch MJ (1997) Distribution of podocyte protein (44 KD) in different types of glomerular diseases. Virchows Arch 431:425–430CrossRefPubMedGoogle Scholar
  77. 77.
    Srivastava T, Garola RE, Whiting JM, Alon US (2001) Synaptopodin expression in idiopathic nephrotic syndrome of childhood. Kidney Int 59:118–125CrossRefPubMedGoogle Scholar
  78. 78.
    Barisoni L, Kriz W, Mundel P, D’Agati V (1999) The dysregulated podocyte phenotype: a novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 10:51–61PubMedGoogle Scholar
  79. 79.
    Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, Yamada Y, Chiba H, Hirohashi S (1998) Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion [published erratum appears in J Cell Biol 1998 Oct 5;143(1):following 276]. J Cell Biol 140:1383–1393CrossRefPubMedGoogle Scholar
  80. 80.
    Smoyer WE, Mundel P, Gupta A, Welsh MJ (1997) Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am J Physiol 273:F150–157PubMedGoogle Scholar
  81. 81.
    Pollak MR (2002) Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint. J Am Soc Nephrol 13:3016–3023PubMedGoogle Scholar
  82. 82.
    Goto H, Wakui H, Komatsuda A, Ohtani H, Imai H, Sawada K, Kobayashi R (2003) Renal alpha-actinin-4: purification and puromycin aminonucleoside-binding property. Nephron Exp Nephrol 93:e27–35CrossRefPubMedGoogle Scholar
  83. 83.
    Arrondel C, Vodovar N, Knebelmann B, Grunfeld JP, Gubler MC, Antignac C, Heidet L (2002) Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J Am Soc Nephrol 13:65–74PubMedGoogle Scholar
  84. 84.
    Togawa A, Miyoshi J, Ishizaki H, Tanaka M, Takakura A, Nishioka H, Yoshida H, Doi T, Mizoguchi A, Matsuura N, Niho Y, Nishimune Y, Nishikawa S, Takai Y (1999) Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha. Oncogene 18:5373–5380CrossRefPubMedGoogle Scholar
  85. 85.
    Kriz W, Gretz N, Lemley KV (1998) Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 54:687–697PubMedGoogle Scholar
  86. 86.
    Le Hir M, Keller C, Eschmann V, Hahnel B, Hosser H, Kriz W (2001) Podocyte bridges between the tuft and Bowman’s capsule: an early event in experimental crescentic glomerulonephritis. J Am Soc Nephrol 12:2060–2071PubMedGoogle Scholar
  87. 87.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860Google Scholar
  88. 88.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869Google Scholar
  89. 89.
    Parving HH, Hommel E, Jensen BR, Hansen HP (2001) Long-term beneficial effect of ACE inhibition on diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int 60:228–234CrossRefPubMedGoogle Scholar
  90. 90.
    Gloy J, Henger A, Fischer KG, Nitschke R, Mundel P, Bleich M, Schollmeyer P, Greger R, Pavenstadt H (1997) Angiotensin II depolarizes podocytes in the intact glomerulus of the rat. J Clin Invest 99:2772–2781PubMedGoogle Scholar
  91. 91.
    Mifsud SA, Allen TJ, Bertram JF, Hulthen UL, Kelly DJ, Cooper ME, Wilkinson-Berka JL, Gilbert RE (2001) Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade. Diabetologia 44:878–882CrossRefPubMedGoogle Scholar
  92. 92.
    Bonnet F, Cooper ME, Kawachi H, Allen TJ, Boner G, Cao Z (2001) Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension. Diabetologia 44:874–877PubMedGoogle Scholar
  93. 93.
    Macconi D, Ghilardi M, Bonassi ME, Mohamed EI, Abbate M, Colombi F, Remuzzi G, Remuzzi A (2000) Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats. J Am Soc Nephrol 11:477–489PubMedGoogle Scholar
  94. 94.
    Benigni A, Tomasoni S, Gagliardini E, Zoja C, Grunkemeyer JA, Kalluri R, Remuzzi G (2001) Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis. J Am Soc Nephrol 12:941–948PubMedGoogle Scholar
  95. 95.
    Mimran A, Ribstein J (1999) Angiotensin receptor blockers: pharmacology and clinical significance. J Am Soc Nephrol 10 Suppl 12:S273–277Google Scholar
  96. 96.
    Campbell R, Sangalli F, Perticucci E, Aros C, Viscarra C, Perna A, Remuzzi A, Bertocchi F, Fagiani L, Remuzzi G, Ruggenenti P (2003) Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int 63:1094–1103CrossRefPubMedGoogle Scholar
  97. 97.
    Reeves WB, Andreoli TE (2000) Transforming growth factor beta contributes to progressive diabetic nephropathy. Proc Natl Acad Sci U S A 97:7667–7669CrossRefPubMedGoogle Scholar
  98. 98.
    Wendt T, Tanji N, Guo J, Hudson BI, Bierhaus A, Ramasamy R, Arnold B, Nawroth PP, Yan SF, D’Agati V, Schmidt AM (2003) Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 14:1383–1395PubMedGoogle Scholar
  99. 99.
    Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D’Agati VD, Schmidt AM (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:1123–1137PubMedGoogle Scholar
  100. 100.
    Sharma K, McCue P, Dunn SR (2003) Diabetic kidney disease in the db/db mouse. Am J Physiol Renal Physiol 284:F1138–1144PubMedGoogle Scholar
  101. 101.
    Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D’Agati VD (2000) Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 11:1656–1666PubMedGoogle Scholar

Copyright information

© IPNA 2004

Authors and Affiliations

  1. 1.Division of NephrologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Division of Pediatric Nephrology, Children’s HospitalUniversity of HeidelbergHeidelbergGermany
  3. 3.Massachusetts General Hospital, Renal UnitHarvard Medical SchoolBostonUSA

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