Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Biology of glomerular podocytes

Pierre Ronco, MD, PhD
Section Editors
Richard J Glassock, MD, MACP
Brad H Rovin, MD
Deputy Editor
Albert Q Lam, MD


The healthy kidney filters metabolic byproducts into the urine but prevents the passage of albumin and other larger essential molecules. This selective filtration occurs across the glomerular capillary wall:

Under normal circumstances, the glomerular capillary wall is extremely permeable to water and small solutes, but negligibly to albumin or other proteins of equivalent molecular weight or larger.

Defects in the glomerular capillary wall result in increased permeability to albumin and proteins of similar size or even larger, causing proteinuria.

Electrical potential differences generated by transglomerular flow may modulate the flux of anionic (charged) albumin across the glomerular capillary wall [1].

The traditional view that the glomerular capillary wall hinders the transit of protein is largely based upon micropuncture studies that demonstrated very low concentrations of albumin in Bowman's space in non-nephrotic animals [2,3]. This view has been challenged by newer data that have demonstrated by intravital 2-photon microscopy, much higher concentrations of albumin in Bowman's space than were reported previously [4]. Given the novelty of the technique of intravital multiphoton microscopy (MPM), these observations need to be validated in other systems and species, especially since they substantially alter our understanding of the pathogenesis of proteinuria [5-8].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jan 2017. | This topic last updated: Tue Jan 24 00:00:00 GMT+00:00 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Hausmann R, Kuppe C, Egger H, et al. Electrical forces determine glomerular permeability. J Am Soc Nephrol 2010; 21:2053.
  2. Oken DE, Flamenbaum W. Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats. J Clin Invest 1971; 50:1498.
  3. Tojo A, Endou H. Intrarenal handling of proteins in rats using fractional micropuncture technique. Am J Physiol 1992; 263:F601.
  4. Russo LM, Sandoval RM, 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.
  5. Gekle M. Renal albumin handling: a look at the dark side of the filter. Kidney Int 2007; 71:479.
  6. Birn H, Christensen EI. Renal albumin absorption in physiology and pathology. Kidney Int 2006; 69:440.
  7. Comper WD, Haraldsson B, Deen WM. Resolved: normal glomeruli filter nephrotic levels of albumin. J Am Soc Nephrol 2008; 19:427.
  8. Peti-Peterdi J, Kidokoro K, Riquier-Brison A. Novel in vivo techniques to visualize kidney anatomy and function. Kidney Int 2015; 88:44.
  9. Smithies O. Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function. Proc Natl Acad Sci U S A 2003; 100:4108.
  10. Akilesh S, Huber TB, Wu H, et al. Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc Natl Acad Sci U S A 2008; 105:967.
  11. Dobrinskikh E, Okamura K, Kopp JB, et al. Human podocytes perform polarized, caveolae-dependent albumin endocytosis. Am J Physiol Renal Physiol 2014; 306:F941.
  12. Chung JJ, Huber TB, Gödel M, et al. Albumin-associated free fatty acids induce macropinocytosis in podocytes. J Clin Invest 2015; 125:2307.
  13. Gagliardini E, Conti S, Benigni A, et al. Imaging of the porous ultrastructure of the glomerular epithelial filtration slit. J Am Soc Nephrol 2010; 21:2081.
  14. Kalluri R. Proteinuria with and without renal glomerular podocyte effacement. J Am Soc Nephrol 2006; 17:2383.
  15. Singh A, Satchell SC, Neal CR, et al. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability. J Am Soc Nephrol 2007; 18:2885.
  16. Jefferson JA, Shankland SJ, Pichler RH. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 2008; 74:22.
  17. Suh JH, Miner JH. The glomerular basement membrane as a barrier to albumin. Nat Rev Nephrol 2013; 9:470.
  18. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008; 358:1129.
  19. Clement LC, Avila-Casado C, Macé C, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 2011; 17:117.
  20. Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 2001; 108:1583.
  21. Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 2006; 354:1387.
  22. Kestilä M, Lenkkeri U, Männikkö M, et al. Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. Mol Cell 1998; 1:575.
  23. Donoviel DB, Freed DD, Vogel H, et al. Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol 2001; 21:4829.
  24. Sellin L, Huber TB, Gerke P, et al. NEPH1 defines a novel family of podocin interacting proteins. FASEB J 2003; 17:115.
  25. Ihalmo P, Palmén T, Ahola H, et al. Filtrin is a novel member of nephrin-like proteins. Biochem Biophys Res Commun 2003; 300:364.
  26. Barletta GM, Kovari IA, Verma RK, et al. Nephrin and Neph1 co-localize at the podocyte foot process intercellular junction and form cis hetero-oligomers. J Biol Chem 2003; 278:19266.
  27. Ciani L, Patel A, Allen ND, ffrench-Constant C. Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol 2003; 23:3575.
  28. 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.
  29. Reiser J, Polu KR, Möller CC, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005; 37:739.
  30. Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005; 308:1801.
  31. Fukasawa H, Bornheimer S, Kudlicka K, Farquhar MG. Slit diaphragms contain tight junction proteins. J Am Soc Nephrol 2009; 20:1491.
  32. Itoh M, Nakadate K, Horibata Y, et al. The structural and functional organization of the podocyte filtration slits is regulated by Tjp1/ZO-1. PLoS One 2014; 9:e106621.
  33. 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.
  34. Huber TB, Kottgen M, Schilling B, et al. Interaction with podocin facilitates nephrin signaling. J Biol Chem 2001; 276:41543.
  35. Huber TB, Schermer B, Müller RU, et al. Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci U S A 2006; 103:17079.
  36. 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.
  37. Uchida K, Suzuki K, Iwamoto M, et al. Decreased tyrosine phosphorylation of nephrin in rat and human nephrosis. Kidney Int 2008; 73:926.
  38. Jones N, New LA, Fortino MA, et al. Nck proteins maintain the adult glomerular filtration barrier. J Am Soc Nephrol 2009; 20:1533.
  39. Rinschen MM, Wu X, König T, et al. Phosphoproteomic analysis reveals regulatory mechanisms at the kidney filtration barrier. J Am Soc Nephrol 2014; 25:1509.
  40. Hartleben B, Schweizer H, Lübben P, et al. Neph-Nephrin proteins bind the Par3-Par6-atypical protein kinase C (aPKC) complex to regulate podocyte cell polarity. J Biol Chem 2008; 283:23033.
  41. Huber TB, Hartleben B, Winkelmann K, et al. Loss of podocyte aPKClambda/iota causes polarity defects and nephrotic syndrome. J Am Soc Nephrol 2009; 20:798.
  42. Hirose T, Satoh D, Kurihara H, et al. An essential role of the universal polarity protein, aPKClambda, on the maintenance of podocyte slit diaphragms. PLoS One 2009; 4:e4194.
  43. 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.
  44. Endlich N, Schordan E, Cohen CD, et al. Palladin is a dynamic actin-associated protein in podocytes. Kidney Int 2009; 75:214.
  45. Ichimura K, Kurihara H, Sakai T. Actin filament organization of foot processes in rat podocytes. J Histochem Cytochem 2003; 51:1589.
  46. Rastaldi MP, Armelloni S, Berra S, et al. Glomerular podocytes contain neuron-like functional synaptic vesicles. FASEB J 2006; 20:976.
  47. Prabakaran T, Nielsen R, Larsen JV, et al. Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease. PLoS One 2011; 6:e25065.
  48. Bechtel W, Helmstädter M, Balica J, et al. Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J Am Soc Nephrol 2013; 24:727.
  49. Prabakaran T, Christensen EI, Nielsen R, Verroust PJ. Cubilin is expressed in rat and human glomerular podocytes. Nephrol Dial Transplant 2012; 27:3156.
  50. Yamamoto-Nonaka K, Koike M, Asanuma K, et al. Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD. J Am Soc Nephrol 2016; 27:2685.
  51. Mallipattu SK, Horne SJ, D'Agati V, et al. Krüppel-like factor 6 regulates mitochondrial function in the kidney. J Clin Invest 2015; 125:1347.
  52. Wang W, Wang Y, Long J, et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 2012; 15:186.
  53. Ayanga BA, Badal SS, Wang Y, et al. Dynamin-Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic Nephropathy. J Am Soc Nephrol 2016; 27:2733.
  54. Ising C, Koehler S, Brähler S, et al. Inhibition of insulin/IGF-1 receptor signaling protects from mitochondria-mediated kidney failure. EMBO Mol Med 2015; 7:275.
  55. Hartleben B, Gödel M, Meyer-Schwesinger C, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest 2010; 120:1084.
  56. Kawakami T, Gomez IG, Ren S, et al. Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS. J Am Soc Nephrol 2015; 26:1040.
  57. Zeng C, Fan Y, Wu J, et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J Pathol 2014; 234:203.
  58. Kriz W, Shirato I, Nagata M, et al. The podocyte's response to stress: the enigma of foot process effacement. Am J Physiol Renal Physiol 2013; 304:F333.
  59. Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 2008; 14:931.
  60. Fornoni A, Sageshima J, Wei C, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 2011; 3:85ra46.
  61. 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.
  62. Michaud JL, Chaisson KM, Parks RJ, Kennedy CR. FSGS-associated alpha-actinin-4 (K256E) impairs cytoskeletal dynamics in podocytes. Kidney Int 2006; 70:1054.
  63. Krendel M, Kim SV, Willinger T, et al. Disruption of Myosin 1e promotes podocyte injury. J Am Soc Nephrol 2009; 20:86.
  64. Kao WH, Klag MJ, Meoni LA, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40:1185.
  65. Kopp JB, Smith MW, Nelson GW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008; 40:1175.
  66. Hussain S, Romio L, Saleem M, et al. Nephrin deficiency activates NF-kappaB and promotes glomerular injury. J Am Soc Nephrol 2009; 20:1733.
  67. Jarad G, Cunningham J, Shaw AS, Miner JH. Proteinuria precedes podocyte abnormalities inLamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest 2006; 116:2272.
  68. Chen Z, Migeon T, Verpont MC, et al. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease. J Am Soc Nephrol 2016; 27:1042.
  69. Jones N, Blasutig IM, Eremina V, et al. Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 2006; 440:818.
  70. New LA, Martin CE, Scott RP, et al. Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture. J Am Soc Nephrol 2016; 27:2422.
  71. Schafer DA. Regulating actin dynamics at membranes: a focus on dynamin. Traffic 2004; 5:463.
  72. Merrifield CJ, Feldman ME, Wan L, Almers W. Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits. Nat Cell Biol 2002; 4:691.
  73. Reiser J, Oh J, Shirato I, et al. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem 2004; 279:34827.
  74. Sever S, Altintas MM, Nankoe SR, et al. Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest 2007; 117:2095.
  75. Wei C, Möller CC, Altintas MM, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14:55.
  76. Shankland SJ. The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006; 69:2131.
  77. Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Lancet 2015; 385:1983.
  78. Bruggeman LA, Ross MD, Tanji N, et al. Renal epithelium is a previously unrecognized site of HIV-1 infection. J Am Soc Nephrol 2000; 11:2079.
  79. Winston JA, Bruggeman LA, Ross MD, et al. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med 2001; 344:1979.
  80. Sunamoto M, Husain M, He JC, et al. Critical role for Nef in HIV-1-induced podocyte dedifferentiation. Kidney Int 2003; 64:1695.
  81. He JC, Husain M, Sunamoto M, et al. Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways. J Clin Invest 2004; 114:643.
  82. Husain M, D'Agati VD, He JC, et al. HIV-1 Nef induces dedifferentiation of podocytes in vivo: a characteristic feature of HIVAN. AIDS 2005; 19:1975.
  83. Zhong J, Zuo Y, Ma J, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int 2005; 68:1048.
  84. Zuo Y, Matsusaka T, Zhong J, et al. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol 2006; 17:2832.
  85. Shah SN, He CJ, Klotman P. Update on HIV-associated nephropathy. Curr Opin Nephrol Hypertens 2006; 15:450.
  86. Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med 2002; 136:604.
  87. Sharma M, Sharma R, Greene AS, et al. Documentation of angiotensin II receptors in glomerular epithelial cells. Am J Physiol 1998; 274:F623.
  88. Hoffmann S, Podlich D, Hähnel B, et al. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol 2004; 15:1475.
  89. Riediger F, Quack I, Qadri F, et al. Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol 2011; 22:2193.
  90. Mayrhofer C, Krieger S, Huttary N, et al. Alterations in fatty acid utilization and an impaired antioxidant defense mechanism are early events in podocyte injury: a proteomic analysis. Am J Pathol 2009; 174:1191.
  91. Sharma K, Ramachandrarao S, Qiu G, et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 2008; 118:1645.
  92. Dai C, Stolz DB, Kiss LP, et al. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol 2009; 20:1997.
  93. Giardino L, Armelloni S, Corbelli A, et al. Podocyte glutamatergic signaling contributes to the function of the glomerular filtration barrier. J Am Soc Nephrol 2009; 20:1929.
  94. Niranjan T, Bielesz B, Gruenwald A, et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 2008; 14:290.
  95. El Machhour F, Keuylian Z, Kavvadas P, et al. Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease. J Am Soc Nephrol 2015; 26:1561.
  96. Canaud G, Bienaimé F, Viau A, et al. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med 2013; 19:1288.
  97. Harvey SJ, Jarad G, Cunningham J, et al. Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease. J Am Soc Nephrol 2008; 19:2150.
  98. Shi S, Yu L, Chiu C, et al. Podocyte-selective deletion of dicer induces proteinuria and glomerulosclerosis. J Am Soc Nephrol 2008; 19:2159.
  99. Kim YH, Goyal M, Kurnit D, et al. Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int 2001; 60:957.
  100. Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int 2005; 67:404.
  101. 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.
  102. Lemley KV, Lafayette RA, Safai M, et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int 2002; 61:1475.
  103. Topham PS, Kawachi H, Haydar SA, et al. Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin. J Clin Invest 1999; 104:1559.
  105. Good KS, O'Brien K, Schulman G, et al. Unexplained nephrotic-range proteinuria in a 38-year-old man: a case of "no change disease". Am J Kidney Dis 2004; 43:933.
  106. Branten AJ, van den Born J, Jansen JL, et al. Familial nephropathy differing from minimal change nephropathy and focal glomerulosclerosis. Kidney Int 2001; 59:693.
  107. Morigi M, Buelli S, Angioletti S, et al. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol 2005; 166:1309.