Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The role of the podocyte in albumin filtration

Abstract

In the past decade, our understanding of the role of podocytes in the function of the glomerular filtration barrier, and of the role of podocyte injury in the pathogenesis of proteinuric kidney disease, has substantially increased. Landmark genetic studies identified mutations in genes expressed by podocytes as a cause of albuminuria and nephrotic syndrome, leading to breakthrough discoveries from many laboratories. These discoveries contributed to a dramatic change in our view of the glomerular filtration barrier of the kidney and of the role of podocyte injury in the development of albuminuria and progressive kidney disease. In the past several years, studies have demonstrated that podocyte injury is a major cause of marked albuminuria and nephrotic syndrome, and have confirmed that podocytes are important for the maintenance of an intact glomerular filtration barrier. An essential role of loss of these cells in the pathogenesis of glomerulosclerosis and progressive proteinuric kidney disease has also been identified. In this Review, we discuss the importance of podocytes for the maintenance of an intact glomerular filtration barrier and their role in albumin handling.

Key Points

  • Podocytes are highly dynamic, terminally differentiated cells that interact with the glomerular basement membrane (GBM) and communicate through signalling at the slit diaphragm

  • The glomerular filtration barrier is composed of podocytes, the GBM and endothelial cells; damage to any of these layers might result in albuminuria

  • Podocyte integrity is essential for maintenance of an intact glomerular filtration barrier and podocyte injury is a major cause of marked albuminuria

  • Several pathogenic mechanisms that are involved in podocyte injury lead to ultrastructural changes in podocytes (that is, podocyte foot process effacement) and proteinuria

  • In the past few years, exciting advances in technology have enabled visualization of the ultrastructure of living podocytes

  • These advances have paved the way for an entirely new field of research aimed at understanding the mechanisms of podocyte foot process effacement

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: High-power electron microscopy image of murine podocyte foot processes attached to the glomerular basement membrane.
Figure 2: The role of podocyte dysfunction in proteinuria.
Figure 3: Light-microscopic image of podocyte ultrastructure created using genetically modified mice in combination with advanced imaging technologies.

References

  1. Haraldsson, B., Nyström, J. & Deen, W. M. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 88, 451–487 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Pavenstädt, H., Kriz, W. & Kretzler, M. Cell biology of the glomerular podocyte. Physiol. Rev. 83, 253–307 (2003).

    Article  PubMed  Google Scholar 

  3. Miner, J. H., Go, G., Cunningham, J., Patton, B. L. & Jarad, G. Transgenic isolation of skeletal muscle and kidney defects in laminin β2 mutant mice: implications for Pierson syndrome. Development 133, 967–975 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Abrahamson, D. R., Hudson, B. G., Stroganova, L., Borza, D. B. & St John, P. L. Cellular origins of type IV collagen networks in developing glomeruli. J. Am. Soc. Nephrol. 20, 1471–1479 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Eremina, V. & Quaggin, S. E. The role of VEGF-A in glomerular development and function. Curr. Opin. Nephrol. Hypertens. 13, 9–15 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Satchell, S. C., Anderson, K. L. & Mathieson, P. W. Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties. J. Am. Soc. Nephrol. 15, 566–574 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Satchell, S. C. et al. Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor. J. Am. Soc. Nephrol. 13, 544–550 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Akilesh, S. et al. Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc. Natl Acad. Sci. USA 105, 967–972 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Farquhar, M. G., Wissig, S. L. & Palade, G. E. Glomerular permeability. I. Ferritin transfer across the normal glomerular capillary wall. J. Exp. Med. 113, 47–66 (1961).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. James, J. A. & Ashworth, C. T. Some features of glomerular filtration and permeability revealed by electron microscopy after intraperitoneal injection of dextran in rats. Am. J. Pathol. 38, 515–525 (1961).

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Benzing, T. Signaling at the slit diaphragm. J. Am. Soc. Nephrol. 15, 1382–1391 (2004).

    Article  PubMed  Google Scholar 

  12. Huber, T. B. & Benzing, T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr. Opin. Nephrol. Hypertens. 14, 211–216 (2005).

    Article  PubMed  Google Scholar 

  13. Ly, J., Alexander, M. & Quaggin, S. E. A podocentric view of nephrology. Curr. Opin. Nephrol. Hypertens. 13, 299–305 (2004).

    Article  PubMed  Google Scholar 

  14. Mundel, P. & Shankland, S. J. Podocyte biology and response to injury. J. Am. Soc. Nephrol. 13, 3005–3015 (2002).

    Article  PubMed  Google Scholar 

  15. Kriz, W., Gretz, N., & Lemley, K. V. Progression of glomerular diseases: is the podocyte the culprit? Kidney Int. 54, 687–697 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Farquhar, M. G. & Palade, G. E. Glomerular permeability. II. Ferritin transfer across the glomerular capillary wall in nephrotic rats. J. Exp. Med. 114, 699–716 (1961).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Caulfield, J. P. & Farquhar, M. G. The permeability of glomerular capillaries of aminonuceoside nephrotic rats to graded dextrans. J. Exp. Med. 142, 61–83 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Rodewald, R. & Karnovsky, M. J. Porous substructure of the glomerular slit diaphragm in the rat and mouse. J. Cell Biol. 60, 423–433 (1974).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Ryan, G. B. & Karnovsky, M. J. An ultrastructural study of the mechanisms of proteinuria in aminonucleoside nephrosis. Kidney Int. 8, 219–232 (1975).

    Article  CAS  PubMed  Google Scholar 

  20. Tojo, A. & Endou, H. Intrarenal handling of proteins in rats using fractional micropuncture technique. Am. J. Physiol. 263, F601–F606 (1992).

    CAS  PubMed  Google Scholar 

  21. Schermer, B. & Benzing, T. Lipid-protein interactions along the slit diaphragm of podocytes. J. Am. Soc. Nephrol. 20, 473–478 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Kestilä, M. et al. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol. Cell 1, 575–582 (1998).

    Article  PubMed  Google Scholar 

  23. Holzman, L. B. et al. Nephrin localizes to the slit pore of the glomerular epithelial cell. Kidney Int. 56, 1481–1491 (1999).

    Article  PubMed  Google Scholar 

  24. Ruotsalainen, V. et al. Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc. Natl Acad. Sci. USA 96, 7962–7967 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Huber, T. B., Kottgen, M., Schilling, B., Walz, G. & Benzing, T. Interaction with podocin facilitates nephrin signaling. J. Biol. Chem. 276, 41543–41546 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Gerke, P., Huber, T. B., Sellin, L., Benzing, T. & Walz, G. Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1. J. Am. Soc. Nephrol. 14, 918–926 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Huber, T. B. et al. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol. Cell. Biol. 23, 4917–4928 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Huber, T. B. et al. The carboxyl terminus of Neph family members binds to the PDZ domain protein zonula occludens-1. J. Biol. Chem. 278, 13417–13421 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Huber, T. B. et al. Molecular basis of the functional podocin–nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum. Mol. Genet. 12, 3397–3405 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Verma, R. et al. Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin. J. Biol. Chem. 278, 20716–20723 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Verma, R. et al. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin. Invest. 116, 1346–1359 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Jones, N. et al. Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 440, 818–823 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Kerjaschki, D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J. Clin. Invest. 108, 1583–1587 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Johnstone, D. B. & Holzman, L. B. Clinical impact of research on the podocyte slit diaphragm. Nat. Clin. Pract. Nephrol. 2, 271–282 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Johnson, R. I., Sedgwick, A., D' Souza-Schorey, C. & Cagan, R. L. Role for a Cindr-Arf6 axis in patterning emerging epithelia. Mol. Biol. Cell 22, 4513–4526 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Bao, S. & Cagan, R. Preferential adhesion mediated by hibris and roughest regulates morphogenesis and patterning in the Drosophila eye. Dev. Cell 8, 925–935 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Höhne, M. et al. The BAR domain protein PICK1 regulates cell recognition and morphogenesis by interacting with Neph proteins. Mol. Cell. Biol. 31, 3241–3251 (2011).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Sugie, A., Umetsu, D., Yasugi, T., Fischback, K. F. & Tabata, T. Recognition of pre- and postsynaptic neurons via nephrin/NEPH1 homologs is a basis for the formation of the Drosophila retinotopic map. Development 137, 3303–3313 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Ramos, R. G. et al. The irregular chiasm C-roughest locus of Drosophila, which affects axonal projections and programmed cell death, encodes a novel immunoglobulin-like protein. Genes Dev. 7, 2533–2547 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Strünkelnberg, M. et al. Rst and its paralogue kirre act redundantly during embryonic muscle development in Drosophila. Development 128, 4229–4239 (2001).

    Article  PubMed  Google Scholar 

  41. Weavers, H. et al. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm. Nature 457, 322–326 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Zhuang, S. et al. Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes. Development 136, 2335–2344 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Cagan, R. L. The Drosophila nephrocyte. Curr. Opin. Nephrol. Hypertens. 20, 409–415 (2011).

    Article  PubMed  Google Scholar 

  44. Fischbach, K. F. et al. The irre cell recognition module (IRM) proteins. J. Neurogenet. 23, 48–67 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Tryggvason, K. Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J. Am. Soc. Nephrol. 10, 2440–2445 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Salmon, A. H. et al. Evidence for restriction of fluid and solute movement across the glomerular capillary wall by the subpodocyte space. Am. J. Physiol. Renal. Physiol. 293: F1777–F1786 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Smithies, O. Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function. Proc. Natl Acad. Sci. USA 100, 4108–4113 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Lazzara, M. J. & Deen, W. M. Model of albumin reabsorption in the proximal tubule. Am. J. Physiol. Renal. Physiol. 292: F430–F439 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Deen, W. M. & Lazzara, M. J. Glomerular filtration of albumin: how small is the sieving coefficient? Kidney Int. Suppl. S63–S64 (2004).

  50. Hausmann, R. et al. Electrical forces determine glomerular permeability. J. Am. Soc. Nephrol. 21, 2053–2058 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Hildebrandt, F. Genetic kidney diseases. Lancet 375, 1287–1295 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Machuca, E., Benoit, G. & Antignac, C. Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum. Mol. Genet. 18, R185–R194 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Moller, C. C., Pollak, M. R. & Reiser, J. The genetic basis of human glomerular disease. Adv. Chronic Kidney Dis. 13, 166–173 (2006).

    Article  PubMed  Google Scholar 

  54. Boyer, O. et al. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. N. Engl. J. Med. 365, 2377–2388 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Brown, E. J. et al. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat. Genet. 42, 72–76 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Boyer, O. et al. Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J. Am. Soc. Nephrol. 22, 239–245 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Barbaux, S. et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat. Genet. 17, 467–470 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Pelletier, J. et al. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys–Drash syndrome. Cell 67, 437–447 (1991).

    Article  CAS  PubMed  Google Scholar 

  59. Denamur, E. et al. WT1 splice-site mutations are rarely associated with primary steroid-resistant focal and segmental glomerulosclerosis. Kidney Int. 57, 1868–1872 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Hinkes, B. et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat. Genet. 38, 1397–1405 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Gbadegesin, R. et al. Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol. Dial. Transplant. 23, 1291–1297 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Machuca, E. et al. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J. Am. Soc. Nephrol. 21, 1209–1217 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Boute, N. et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat. Genet. 24, 349–354 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Jungraithmayr, T. C. et al. Screening for NPHS2 mutations may help predict FSGS recurrence after transplantation. J. Am. Soc. Nephrol. 22, 579–585 (2011).

    Article  PubMed Central  PubMed  Google Scholar 

  65. Weber, S. et al. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int. 66, 571–579 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Reiser, J. et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat. Genet. 37, 739–744 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Winn, M. P. et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308, 1801–1804 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Kaplan, J. M. et al. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat. Genet. 24, 251–256 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Roselli, S. et al. Podocin localizes in the kidney to the slit diaphragm area. Am. J. Pathol. 160, 131–139 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Huber, T. B., Schermer, B. & Benzing, T. Podocin organizes ion channel-lipid supercomplexes: implications for mechanosensation at the slit diaphragm. Nephron Exp. Nephrol. 106, e27–e31 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Huber, T. B. et al. Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc. Natl Acad. Sci. USA 103, 17079–17086 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Goodman, M. B. et al. MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation. Nature 415, 1039–1042 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Huang, M., Gu, G., Ferguson, E. L. & Chalfie, M. A stomatin-like protein necessary for mechanosensation in C. elegans. Nature 378, 292–295 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. Huber, T. B. et al. Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin. J. Clin. Invest. 116, 1337–1345 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Dryer, S. E. & Reiser, J. TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am. J. Physiol. Renal Physiol. 299, F689–F701 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Shankland, S. J. The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 69, 2131–2147 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Kriz, W., Shirato, I., Nagata, M., Lehir, M. & Lemley, K. V. The podocyte's response to stress: the enigma of foot process effacement. Am. J. Physiol. Renal Physiol. 304, F333–F347 (2012).

    Article  PubMed  CAS  Google Scholar 

  78. Clement, L. C. et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat. Med. 17, 117–122 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Jin, J. et al. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 151, 384–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Eremina, V. et al. Vascular endothelial growth factor a signaling in the podocyte–endothelial compartment is required for mesangial cell migration and survival. J. Am. Soc. Nephrol. 17, 724–735 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Eremina, V. et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358, 1129–1136 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Thadhani, R. et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 124, 940–950 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Faul, C. et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat. Med. 14, 931–938 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Jiang, L. et al. Over-expressing transient receptor potential cation channel 6 in podocytes induces cytoskeleton rearrangement through increases of intracellular Ca2+ and RhoA activation. Exp. Biol. Med. (Maywood) 236, 184–193 (2011).

    Article  CAS  Google Scholar 

  87. Tian, D. et al. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci. Signal. 3, ra77 (2010).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Faul, C., Asanuma, K., Yanagida-Asanuma, E., Kim, K. & Mundel, P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 17, 428–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Shibata, S. et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat. Med. 14, 1370–1376 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Scott, R. P. et al. Podocyte-specific loss of Cdc42 leads to congenital nephropathy. J. Am. Soc. Nephrol. 23, 1149–1154 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Wang, L. et al. Mechanisms of the proteinuria induced by Rho GTPases. Kidney Int. 81, 1075–1085 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Zhu, L., Jiang, R., Aoudjit, L., Jones, N. & Takano, T. Activation of RhoA in podocytes induces focal segmental glomerulosclerosis. J. Am. Soc. Nephrol. 22, 1621–1630 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Ciná, D. P. et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J. Am. Soc. Nephrol. 23, 412–420 (2012).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Letavernier, E. & Legendre, C. mToR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant. Rev. (Orlando) 22, 125–130 (2008).

    Article  Google Scholar 

  96. Inoki, K. et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121, 2181–2196 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Gödel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  98. Brahler, S. et al. Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. Am. J. Physiol. Renal. Physiol. 303, F1473–F1485 (2012).

    Article  PubMed  CAS  Google Scholar 

  99. Mathieson, P. W. Proteinuria and immunity—an overstated relationship? N. Engl. J. Med. 359, 2492–2494 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Hussain, S. et al. Nephrin deficiency activates NF-κB and promotes glomerular injury. J. Am. Soc. Nephrol. 20, 1733–1743 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Garg, P. & Holzman, L. B. Podocytes: gaining a foothold. Exp. Cell Res. 318, 955–963 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Hirose, T. et al. An essential role of the universal polarity protein, aPKCλ, on the maintenance of podocyte slit diaphragms. PLoS ONE 4, e4194 (2009).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  103. Huber, T. B. et al. Loss of podocyte aPKCλ/ι causes polarity defects and nephrotic syndrome. J. Am. Soc. Nephrol. 20, 798–806 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Hartleben, B. et al. Role of the polarity protein Scribble for podocyte differentiation and maintenance. PLoS ONE 7, e36705 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Hartleben, B. et al. Neph-Nephrin proteins bind the Par3–Par6–atypical protein kinase C (aPKC) complex to regulate podocyte cell polarity. J. Biol. Chem. 283, 23033–23038 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Brinkkoetter, P. T. et al. Cyclin I activates Cdk5 and regulates expression of Bcl-2 and Bcl-XL in postmitotic mouse cells. J. Clin. Invest. 119, 3089–3101 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Brinkkoetter, P. T. et al. p35, the non-cyclin activator of Cdk5, protects podocytes against apoptosis in vitro and in vivo. Kidney Int. 77, 690–699 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Susztak, K., Raff, A. C., Schiffer, M. & Böttinger, E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Schiffer, M. et al. Apoptosis in podocytes induced by TGF-β and Smad7. J. Clin. Invest. 108, 807–816 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Wharram, B. L. et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J. Am. Soc. Nephrol. 16, 2941–2952 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Cheung, Z. H., Gong, K. & Ip, N. Y. Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J. Neurosci. 28, 4872–4877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Najafian, B., Alpers, C. E. & Fogo, A. B. Pathology of human diabetic nephropathy. Contrib. Nephrol. 170, 36–47 (2011).

    Article  PubMed  Google Scholar 

  113. Hara, M., Yanagihara, T. & Kihara, I. Cumulative excretion of urinary podocytes reflects disease progression in IgA nephropathy and Schönlein–Henoch purpura nephritis. Clin. J. Am. Soc. Nephrol. 2, 231–238 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Höhne, M. et al. Light microscopic visualization of podocyte ultrastructure demonstrates oscillating glomerular contractions. Am. J. Pathol. 182, 332–338 (2012).

    Article  PubMed  Google Scholar 

  115. Grgic, I. et al. Imaging of podocyte foot processes by fluorescence microscopy. J. Am. Soc. Nephrol. 23, 785–791 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Peti-Peterdi, J. & Sipos, A. A high-powered view of the filtration barrier. J. Am. Soc. Nephrol. 21, 1835–1841 (2010).

    Article  PubMed  Google Scholar 

  117. Peti-Peterdi, J., Burford, J. L. & Hackl, M. J. The first decade of using multiphoton microscopy for high-power kidney imaging. Am. J. Physiol. Renal Physiol. 302, F227–F233 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Nakano, D. et al. Multiphoton imaging of the glomerular permeability of angiotensinogen. J. Am. Soc. Nephrol. 23, 1847–1856 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  119. Mangos, S. & Reiser, J. Fishing for new glomerular disease-related genes. J. Am. Soc. Nephrol. 22, 1960–1962 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Mathieson, P. W. The podocyte as a target for therapies—new and old. Nat. Rev. Nephrol. 8, 52–56 (2012).

    Article  CAS  Google Scholar 

  121. Muller, R. U. & Benzing, T. A photo shoot of proteinuria: zebrafish models of inducible podocyte damage. J. Am. Soc. Nephrol. 23, 969–971 (2012).

    Article  PubMed  CAS  Google Scholar 

  122. Kramer-Zucker, A. G., Wiessner, S., Jensen, A. M. & Drummond, I. A. Organization of the pronephric filtration apparatus in zebrafish requires Nephrin, Podocin and the FERM domain protein Mosaic eyes. Dev. Biol. 285, 316–329 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  123. Hentschel, D. M. et al. Rapid screening of glomerular slit diaphragm integrity in larval zebrafish. Am. J. Physiol. Renal Physiol. 293, F1746–F1750 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Zhou, W. & Hildebrandt, F. Inducible podocyte injury and proteinuria in transgenic zebrafish. J. Am. Soc. Nephrol. 23, 1039–1047 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Kim, J. M. et al. CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility. Science 23, 1298–1300 (2003).

    Article  CAS  Google Scholar 

  126. Zenker, M. et al. Human laminin β2 deficiency causes congenital nephrosis with mesangial sclerosis and disinct eye abnormalities. Hum. Mol. Genet. 13, 2625–2632 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Mele, C. et al. MYO1E mutations and childhood familial focal segmenal glomerulosclerosis. N. Engl. J. Med. 365, 295–306 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Heeringa, S. F. et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J. Clin. Invest. 121, 2013–2024 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Ozaltin, F. et al. Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am. J. Hum. Genet. 89, 139–147 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Habib, R. et al. The nephropathy associated with male pseudohermaphroditism and Wilms' tumor (Drash syndrome): a distinctive glomerular lesion—report of 10 cases. Clin. Nephrol. 24, 269–278 (1985).

    CAS  PubMed  Google Scholar 

  131. Seri, M. et al. Mutations in MYH9 result in the May-Hegglin anomaly, and Fectner and Sebastian Syndromes. Nat. Genet. 26, 103–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Dreyer, S. D. et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat. Genet. 19, 47–50 (1998).

    Article  CAS  PubMed  Google Scholar 

  133. McIntosh, I. et al. Mutation analysis of LMX1B gene in nail patella syndrome patients. Am. J. Hum. Genet. 63, 1651–1658 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Vollrath, D. et al. Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. Hum. Mol. Genet. 7, 1091–1098 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Boerkoel, C. F. et al. Mutant chromatin remodelling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat. Genet. 30, 215–220 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Quinzii, C. et al. A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am. J. Hum. Genet. 78, 345–349 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Salviati, L. et al. Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 65, 606–608 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. López, L. C. et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl disphosphate synthase subunit 2 (PDSS2) mutations. Am. J. Hum. Genet. 79, 1125–1129 (2006).

    Article  PubMed Central  PubMed  Google Scholar 

  139. Kurogouchi, F. et al. A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am. J. Nephrol. 18, 551–556 (1998).

    Article  CAS  PubMed  Google Scholar 

  140. Goto, Y., Nonaka, I. & Horai, S. A mutation in the tRNALeu(URR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature, 348, 651–653 (1990).

    Article  CAS  PubMed  Google Scholar 

  141. Balreira, A. et al. A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome. Hum. Mol. Genet. 17, 2238–2243 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Berkovic, S. F. et al. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am. J. Hum. Genet. 82, 673–684 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Castelletti, F. et al. Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc.Natl. Acad. Sci. USA 105, 2538–2543 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' work is supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 635 [T. Benzing] and BR2955 [P. T. Brinkkoetter]). Podocyte research has benefited from the contribution of many groups all over the world and we apologize to those colleagues whose work could not be cited due to space limitations.

Author information

Authors and Affiliations

Authors

Contributions

All authors researched the data for the article. T. Benzing and P. T. Brinkkoetter wrote the article and C. Ising reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Thomas Benzing.

Ethics declarations

Competing interests

T. Benzing has received speaker's honoraria from Amgen, Hexal, Novartis and Otsuka. The other authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brinkkoetter, P., Ising, C. & Benzing, T. The role of the podocyte in albumin filtration. Nat Rev Nephrol 9, 328–336 (2013). https://doi.org/10.1038/nrneph.2013.78

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2013.78

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing