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Podocytes and Diabetic Nephropathy

  • George Jerums
  • Sianna Panagiotopoulos
  • Richard MacIsaac
Part of the Contemporary Diabetes book series (CDI)

Abstract

The glomerular capillary wall comprises three major components: the fenestrated endothelium surrounded by glycocalyx, the glomerular basement membrane, and the podocyte layer. Podocytes are specialized epithelial cells that form a network of interdigitating foot processes. The predominant filtration pathway for macromolecules is through slit diaphragms bounded by podocyte foot processes. Nephrin is a key component of the slit diaphragm in association with other intracellular proteins, including CD2-associated protein (CD2AP), podocin, and α-actinin IV (Fig. 1). Together, these proteins contribute to the role of the slit diaphragm as the major size-selective filtration barrier.

Keywords

Vascular Endothelial Growth Factor Diabetic Nephropathy Glomerular Basement Membrane Albumin Excretion Rate Slit Diaphragm 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Wartiovaara J, Ofverstedt LG, Khoshnoodi J, et al. Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. J Clin Invest 2004;114:1475–1483.PubMedCrossRefGoogle Scholar
  2. 2.
    Patrakka J, Kestila M, Wartiovaara J, et al. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int 2000;58:972–980.PubMedCrossRefGoogle Scholar
  3. 3.
    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;24:349–354.PubMedCrossRefGoogle Scholar
  4. 4.
    Shih NY, Li J, Karpitskii V, et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 1999;286:312–315.PubMedCrossRefGoogle Scholar
  5. 5.
    Deen WM. What determines glomerular capillary permeability? J Clin Invest 2004;114:1412–1414.PubMedCrossRefGoogle Scholar
  6. 6.
    Rossi M, Morita H, Sormunen R, et al. Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J 2003;22:236–245.PubMedCrossRefGoogle Scholar
  7. 7.
    Haraldsson B, Sorensson J. Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier. News Physiol Sci 2004;19:7–10.PubMedGoogle Scholar
  8. 8.
    Osterby R, Hartmann A, Nyengaard JR, Bangstad HJ. Development of renal structural lesions in type-1 diabetic patients with microalbuminuria. Observations by light microscopy in 8-year followup biopsies. Virchows Arch 2002;440:94–101.PubMedCrossRefGoogle Scholar
  9. 9.
    Rudberg S, Osterby R, Dahlquist G, Nyberg G, Persson B. Predictors of renal morphological changes in the early stage of microalbuminuria in adolescents with IDDM. Diabetes Care 1997;20:265–271.PubMedCrossRefGoogle Scholar
  10. 10.
    Caramori ML, Kim Y, Huang C, et al. Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes. Diabetes 2002;51:506–513.PubMedCrossRefGoogle Scholar
  11. 11.
    Fioretto P, Steffes MW, Mauer M. Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria. Diabetes 1994;43:1358–1364.PubMedCrossRefGoogle Scholar
  12. 12.
    Ellis EN, Warady BA, Wood EG, et al. Renal structural-functional relationships in early diabetes mellitus. Pediatr Nephrol 1997;11:584–591.PubMedCrossRefGoogle Scholar
  13. 13.
    Ellis EN, Steffes MW, Chavers B, Mauer SM. Observations of glomerular epithelial cell structure in patients with type I diabetes mellitus. Kidney Int 1987;32:736–741.PubMedCrossRefGoogle Scholar
  14. 14.
    Steffes MW, Schmidt D, McCrery R, Basgen JM. Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int 2001;59:2104–2113.PubMedGoogle Scholar
  15. 15.
    White KE, Bilous RW, Marshall SM, et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002;51:3083–3089.PubMedCrossRefGoogle Scholar
  16. 16.
    Pagtalunan ME, Miller PL, Jumping-Eagle S, et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997;99:342–348.PubMedGoogle Scholar
  17. 17.
    Meyer TW, Bennett PH, Nelson RG. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with type II diabetes and microalbuminuria. Diabetologia 1999;42:1341–1344.PubMedCrossRefGoogle Scholar
  18. 18.
    Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P. Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes 2003;52:1031–1035.PubMedCrossRefGoogle Scholar
  19. 19.
    White KE, Bilous RW. Structural alterations to the podocyte are related to proteinuria in type 2 diabetic patients. Nephrol Dial Transplant 2004;19:1437–1440.PubMedCrossRefGoogle Scholar
  20. 20.
    Hirschberg R, Wang S. Proteinuria and growth factors in the development of tubulointerstitial injury and scarring in kidney disease. Curr Opin Nephrol Hypertens 2005;14:43–52.PubMedCrossRefGoogle Scholar
  21. 21.
    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;1:575–582.PubMedCrossRefGoogle Scholar
  22. 22.
    Forbes JM, Bonnet F, Russo LM, et al. Modulation of nephrin in the diabetic kidney: association with systemic hypertension and increasing albuminuria. J Hypertens 2002;20:985–992.PubMedCrossRefGoogle Scholar
  23. 23.
    Bonnet F, Cooper ME, Kawachi H, Allen TJ, Boner G, Cao Z. Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension. Diabetologia 2001;44:874–877.PubMedCrossRefGoogle Scholar
  24. 24.
    Kelly DJ, Aaltonen P, Cox AJ, et al. Expression of the slit-diaphragm protein, nephrin, in experimental diabetic nephropathy: differing effects of anti-proteinuric therapies. Nephrol Dial Transplant 2002;17:1327–1332.PubMedCrossRefGoogle Scholar
  25. 25.
    Mifsud SA, Allen TJ, Bertram JF, et al. Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade. Diabetologia 2001;44:878–882.PubMedCrossRefGoogle Scholar
  26. 26.
    Langham RG, Kelly DJ, Cox AJ, et al. Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition. Diabetologia 2002;45:1572–1576.PubMedCrossRefGoogle Scholar
  27. 27.
    Doublier S, Salvidio G, Lupia E, et al. Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 2003;52:1023–1030.PubMedCrossRefGoogle Scholar
  28. 28.
    Gloy J, Henger A, Fischer KG, et al. Angiotensin II modulates cellular functions of podocytes. Kidney Int Suppl 1998;67:S168–S170.CrossRefGoogle Scholar
  29. 29.
    Tryggvason K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol 1999;10:2440–2445.PubMedGoogle Scholar
  30. 30.
    Osicka TM, Kiriazis Z, Pratt LM, Jerums G, Comper WD. Ramipril and aminoguanidine restore renal lysosomal processing in streptozotocin diabetic rats. Diabetologia 2001;44:230–236.PubMedCrossRefGoogle Scholar
  31. 31.
    Miner JH. Renal basement membrane components. Kidney Int 1999;56:2016–2024.PubMedCrossRefGoogle Scholar
  32. 32.
    Martin J, Steadman R, Knowlden J, Williams J, Davies M. Differential regulation of matrix metalloproteinases and their inhibitors in human glomerular epithelial cells in vitro. J Am Soc Nephrol 1998;9:1629–1637.PubMedGoogle Scholar
  33. 33.
    Kitsiou PV, Tzinia AK, Stetler-Stevenson WG, et al. Glucose-induced changes in integrins and matrix-related functions in cultured human glomerular epithelial cells. Am J Physiol Renal Physiol 2003;284:F671–F679.PubMedGoogle Scholar
  34. 34.
    McLennan SV, Fisher E, Martell SY, et al. Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: possible role in diabetic nephropathy. Kidney Int Suppl 2000;77:S81–S87.CrossRefGoogle Scholar
  35. 35.
    Schena F, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005;16:S30–S33.PubMedCrossRefGoogle Scholar
  36. 36.
    Coward R, Welsh G, Holman G, et al. Human podocytes rapidly utilize glucose by both GLUT1 and GLUT4 in response to insulin; with significant differences in glucose transporter levels occurring in diabetic nephropathy. J Am Soc Nephrol 2003;14:388A.Google Scholar
  37. 37.
    Heilig CW, Liu Y, England RL, et al. d-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy. Diabetes 1997;46:1030–1039.PubMedCrossRefGoogle Scholar
  38. 38.
    Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 1995;96:1802–1814.PubMedGoogle Scholar
  39. 39.
    Mathieson PW. The cellular basis of albuminuria. Clin Sci (Lond) 2004;107:533–538.CrossRefGoogle Scholar
  40. 40.
    Inoki K, Haneda M, Maeda S, Koya D, Kikkawa R. TGF-beta 1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int 1999;55:1704–1712.PubMedCrossRefGoogle Scholar
  41. 41.
    Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA 1993;90:1814–1818.PubMedCrossRefGoogle Scholar
  42. 42.
    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;62:901–913.CrossRefGoogle Scholar
  43. 43.
    Gruden G, Zonca S, Hayward A, et al. Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinasedependent. Diabetes 2000;49:655–661.PubMedCrossRefGoogle Scholar
  44. 44.
    Riser BL, Ladson-Wofford S, Sharba A, et al. TGF-beta receptor expression and binding in rat mesangial cells: modulation by glucose and cyclic mechanical strain. Kidney Int 1999;56:428–439.PubMedCrossRefGoogle Scholar
  45. 45.
    Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci USA 2000;97:8015–8020.PubMedCrossRefGoogle Scholar
  46. 46.
    de Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, Lameire NH. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol 2001;12:993–1000.PubMedGoogle Scholar
  47. 47.
    Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003;162:1123–1137.PubMedGoogle Scholar
  48. 48.
    Khamaisi M, Schrijvers BF, De Vriese AS, Raz I, Flyvbjerg A. The emerging role of VEGF in diabetic kidney disease. Nephrol Dial Transplant 2003;18:1427–1430.PubMedCrossRefGoogle Scholar
  49. 49.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25.PubMedCrossRefGoogle Scholar
  50. 50.
    Gruden G, Perin P, Camussi G. Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology. Curr Diabetes Rev 2005;1:27–40.CrossRefPubMedGoogle Scholar
  51. 51.
    Foster RR, Saleem MA, Mathieson PW, Bates DO, Harper SJ. Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol Renal Physiol 2005;288:F48–F57.PubMedCrossRefGoogle Scholar
  52. 52.
    Chen S, Kasama Y, Lee JS, Jim B, Marin M, Ziyadeh FN. Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. Diabetes 2004;53:2939–2949.PubMedCrossRefGoogle Scholar
  53. 53.
    Hayashida T, Schnaper HW. High ambient glucose enhances sensitivity to TGF-beta1 via extracellular signal—regulated kinase and protein kinase Cdelta activities in human mesangial cells. J Am Soc Nephrol 2004;15:2032–2041.PubMedCrossRefGoogle Scholar
  54. 54.
    Cha DR, Kim NH, Yoon JW, et al. Role of vascular endothelial growth factor in diabetic nephropathy. Kidney Int Suppl 2000;77:S104–S112.CrossRefGoogle Scholar
  55. 55.
    Shulman K, Rosen S, Tognazzi K, Manseau EJ, Brown LF. Expression of vascular permeability factor (VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol 1996;7:661–666.PubMedGoogle Scholar
  56. 56.
    Cooper ME, Vranes D, Youssef S, et al. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 1999;48:2229–2239.PubMedCrossRefGoogle Scholar
  57. 57.
    Tsuchida K, Makita Z, Yamagishi S, et al. Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia 1999;42:579–588.PubMedCrossRefGoogle Scholar
  58. 58.
    Tanji N, Markowitz GS, Fu C, et al. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 2000;11:1656–1666.PubMedGoogle Scholar
  59. 59.
    Anavekar NS, Gans DJ, Berl T, et al. Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria. Kidney Int Suppl 2004:S50–S55.Google Scholar
  60. 60.
    Young RJ, Hoy WE, Kincaid-Smith P, Seymour AE, Bertram JF. Glomerular size and glomerulosclerosis in Australian aborigines. Am J Kidney Dis 2000;36:481–489.PubMedGoogle Scholar
  61. 61.
    Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 1998;54:687–697.PubMedCrossRefGoogle Scholar
  62. 62.
    Durvasula RV, Petermann AT, Hiromura K, et al. Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 2004;65:30–39.PubMedCrossRefGoogle Scholar
  63. 63.
    Schiffer M, Bitzer M, Roberts IS, et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 2001;108:807–816.PubMedCrossRefGoogle Scholar
  64. 64.
    Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev 2003;83:253–307.PubMedGoogle Scholar
  65. 65.
    Chen HC, Chen CA, Guh JY, Chang JM, Shin SJ, Lai YH. Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci 2000;67:2345–2353.PubMedCrossRefGoogle Scholar
  66. 66.
    Krishnamurti U, Rondeau E, Sraer JD, Michael AF, Tsilibary EC. Alterations in human glomerular epithelial cells interacting with nonenzymatically glycosylated matrix. J Biol Chem 1997;272:27,966–27,970.PubMedCrossRefGoogle Scholar
  67. 67.
    Nakamura T, Ushiyama C, Osada S, Hara M, Shimada N, Koide H. Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria. Metabolism 2001;50:1193–1196.PubMedCrossRefGoogle Scholar
  68. 68.
    Christensen EI, Birn H. Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 2002;3:256–266.PubMedGoogle Scholar
  69. 69.
    Osicka TM, Houlihan CA, Chan JG, Jerums G, Comper WD. Albuminuria in patients with type 1 diabetes is directly linked to changes in the lysosome-mediated degradation of albumin during renal passage. Diabetes 2000;49:1579–1584.PubMedCrossRefGoogle Scholar
  70. 70.
    Tojo A, Onozato ML, Kurihara H, Sakai T, Goto A, Fujita T. Angiotensin II blockade restores albumin reabsorption in the proximal tubules of diabetic rats. Hypertens Res 2003;26:413–419.PubMedCrossRefGoogle Scholar
  71. 71.
    Yamazaki H, Saito A, Ooi H, Kobayashi N, Mundel P, Gejyo F. Differentiation-induced cultured podocytes express endocytically active megalin, a heymann nephritis antigen. Nephron Exp Nephrol 2004;96:e52–e58.PubMedCrossRefGoogle Scholar
  72. 72.
    Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol 1995;6:35–47.PubMedGoogle Scholar
  73. 73.
    Kerjaschki D, Exner M, Ullrich R, et al. Pathogenic antibodies inhibit the binding of apolipoproteins to megalin/gp330 in passive Heymann nephritis. J Clin Invest 1997;100:2303–2309.PubMedCrossRefGoogle Scholar
  74. 74.
    Coward RJ, Foster RR, Patton D, et al. Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, Podocin, and CD2 associated protein in cultured human podocytes. J Am Soc Nephrol 2005;16:629–637.PubMedCrossRefGoogle Scholar
  75. 75.
    Bjorn SF, Bangstad HJ, Hanssen KF, et al. Glomerular epithelial foot processes and filtration slits in IDDM patients. Diabetologia 1995;38:1197–1204.PubMedCrossRefGoogle Scholar
  76. 76.
    Berg UB, Torbjornsdotter TB, Jaremko G, Thalme B. Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM. Diabetologia 1998;41:1047–1056.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • George Jerums
    • 1
  • Sianna Panagiotopoulos
    • 2
  • Richard MacIsaac
    • 3
  1. 1.Endocrine Unit and Department of MedicineUniversity of MelbourneMelbourne
  2. 2.Endocrine Unit and Department of MedicineAustin Health and University of MelbourneMelbourne
  3. 3.Endocrine Unit, Department of MedicineUniversity of MelbourneMelbourne

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