Skip to main content

Advertisement

SpringerLink
Log in

The renin-angiotensin system in glomerular podocytes: Mediator of glomerulosclerosis and link to hypertensive nephropathy

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

The renoprotective effects of pharmacologic inhibition of angiotensin II extend beyond the blood pressure-lowering effects alone, consistent with the observation that angiotensin II is produced locally within the kidney and mediates tissue injury through a series of nonhemodynamic effects. Podocytes are terminally differentiated epithelial cells that contribute to the filtration barrier of the kidney, but also safeguard against the development of glomerulosclerosis. Mounting evidence demonstrates that podocytes are not only a local source of angiotensin II production, but are also vulnerable to its deleterious effects, thus fueling the future development of glomerular scarring. In this review article, we explore the role of a local angiotensin system as a mediator of podocyte injury and discuss its potential link to hypertensive renal disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Kincaid-Smith P: Hypothesis: obesity and the insulin resistance syndrome play a major role in end-stage renal failure attributed to hypertension and labelled “hypertensive nephrosclerosis.“ J Hypertens 2004, 22:1051–1055.

    Article  PubMed  CAS  Google Scholar 

  2. Strippoli GF, Craig M, Deeks JJ, et al.: Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004, 329:828.

    Article  PubMed  CAS  Google Scholar 

  3. The GISEN Group: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Gruppo Italiano di Studi Epidemiologici in Nefrologia. Lancet 1997, 349:1857–1863.

    Article  Google Scholar 

  4. Fogo AB: Renal fibrosis and the renin-angiotensin system. Adv Nephrol Necker Hosp 2001, 31:69–87.

    PubMed  CAS  Google Scholar 

  5. Re RN: Mechanisms of disease: local renin-angiotensinaldosterone systems and the pathogenesis and treatment of cardiovascular disease. Nat Clin Pract Cardiovasc Med 2004, 1:42–47.

    PubMed  CAS  Google Scholar 

  6. Seikaly MG, Arant BS, Seney FD: Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest 1990, 86:1352–1357.

    PubMed  CAS  Google Scholar 

  7. Pavenstädt H, Kriz W, Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev 2003, 83:253–307.

    PubMed  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. 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, 1:575–582.

    Article  PubMed  Google Scholar 

  10. Ruf RG, Lichtenberger A, Karle SM, et al.: Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 2004, 15:722–732.

    Article  PubMed  Google Scholar 

  11. Schwarz K, Simons M, Reiser J, et al.: Podocin, a raftassociated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 2001, 108:1621–1629.

    Article  PubMed  CAS  Google Scholar 

  12. Shih NY, Li J, Karpitskii V, et al.: Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 1999, 286:312–315.

    Article  PubMed  CAS  Google Scholar 

  13. Roselli S, Heidet L, Sich M, et al.: Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 2004, 24:550–560.

    Article  PubMed  CAS  Google Scholar 

  14. Benzing T: Signaling at the slit diaphragm. J Am Soc Nephrol 2004, 15:1382–1391. This paper provides a comprehensive review on the role of the slit diaphragm as a signal transduction complex.

    Article  PubMed  Google Scholar 

  15. Yu CC, Yen TS, Lowell CA, et al.: Lupus-like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn. Curr Biol 2001, 11:34–38.

    Article  PubMed  CAS  Google Scholar 

  16. Foster RR, Saleem MA, Mathieson PW, et al.: Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol Renal Physiol 2005, 288:F48-F57.

    Article  PubMed  CAS  Google Scholar 

  17. Schiffer M, Mundel P, Shaw AS, Böttinger EP: A novel role for the adaptor molecule CD2-associated protein in transforming growth factor-beta-induced apoptosis. J Biol Chem 2004, 279:37004–37012.

    Article  PubMed  CAS  Google Scholar 

  18. Steffes MW, Schmidt D, McCrery R, et al.: Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int 2001, 59:2104–2113.

    PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. Kriz W: Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech 2002, 57:189–195.

    Article  PubMed  Google Scholar 

  21. Wharram BL, Goyal M, Wiggins JE, et al.: Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 2005, 16:2941–2952. By reducing podocyte number in a dose-dependent fashion in a transgenic rat model overexpressing human diptheria receptor, the authors provide strong evidence for the role of podocyte depletion in the developmment of glomerulosclerosis.

    Article  PubMed  CAS  Google Scholar 

  22. Sharma M, Sharma R, Greene AS, et al.: Documentation of angiotensin II receptors in glomerular epithelial cells. Am J Physiol 1998, 274:F623-F627.

    PubMed  CAS  Google Scholar 

  23. Liebau MC, Lang D, Bohm J, et al.: Functional expression of the renin angiotensin system in human podocytes. Am J Physiol Renal Physiol 2005, E pub ahead of print.

  24. Xu ZG, Yoo TH, Ryu DR, et al.: Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli. Kidney Int 2005, 67:944–952.

    Article  PubMed  CAS  Google Scholar 

  25. Wolf G, Chen S, Ziyadeh FN: From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 2005, 54:1626–1634.

    Article  PubMed  CAS  Google Scholar 

  26. Bonnet F, Cooper ME, Kawachi H, et al.: Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension. Diabetologia 2001, 44:874–877.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. Davis BJ, Cao Z, de Gasparo M, et al.: Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: potential role of nephrin. J Hypertens 2003, 21:209–216.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. Macconi D, Ghilardi M, Bonassi ME, et al.: Effect of angiotensin-converting enzyme inhibition on glomerular basement membrane permeability and distribution of zonula occludens-1 in MWF rats. J Am Soc Nephrol 2000, 11:477–489.

    PubMed  CAS  Google Scholar 

  31. Mundel P, Shankland SJ: Podocyte biology and response to injury. J Am Soc Nephrol 2002, 13:3005–3015.

    Article  PubMed  Google Scholar 

  32. Kim NH, Rincon-Choles H, Bhandari B, et al.: Redox dependence of glomerular epithelial cell hypertrophy in response to glucose. Am J Physiol Renal Physiol 2005, Epub ahead of print.

  33. Gloy J, Henger A, Fischer KG, et al.: Angiotensin II modulates cellular functions of podocytes. Kidney Int Suppl 1998, 67:S168-S170.

    Article  PubMed  CAS  Google Scholar 

  34. Winn MP, Conlon PJ, Lynn KL, et al.: A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 2005, 308:1801–1804. This study identifies a specific mutation in the calcium channel TRPC6, raising the novel hypothesis that a primary defect in calcium signaling may promote podocyte injury.

    Article  PubMed  CAS  Google Scholar 

  35. Reiser J, Polu KR, Möller CC, et al.: TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 2005, 37:739–744. This study makes the novel observation that TRPC6 is a component of the slit diaphragm complex and identifies additional kindreds of familial FSGS with specific mutations in this calcium channel.

    Article  PubMed  CAS  Google Scholar 

  36. Eremina V, Quaggin SE: The role of VEGF-A in glomerular development and function. Curr Opin Nephrol Hypertens 2004, 13:9–15.

    Article  PubMed  CAS  Google Scholar 

  37. Kakizawa H, Itoh Y, Imamura S, et al.: Possible role of VEGF in the progression of kidney disease in streptozotocin (STZ)-induced diabetic rats: effects of an ACE inhibitor and an angiotensin II receptor antagonist. Horm Metab Res 2004, 36:458–464.

    Article  PubMed  CAS  Google Scholar 

  38. Chen S, Lee JS, Iglesias-de la Cruz MC, et al.: Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy. Nephrol Dial Transplant 2005, 20:1320–1328.

    Article  PubMed  CAS  Google Scholar 

  39. Abbate M, Zoja C, Morigi M, et al.: Transforming growth factor-beta1 is upregulated by podocytes in response to excess intraglomerular passage of proteins: a central pathway in progressive glomerulosclerosis. Am J Pathol 2002, 161:2179–2193.

    PubMed  CAS  Google Scholar 

  40. Ding G, Reddy K, Kapasi AA, et al.: Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am J Physiol Renal Physiol 2002, 283:F173-F180.

    PubMed  CAS  Google Scholar 

  41. 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. This study demonstrates that mechanical forces activate a local angiotensin system in podocytes by increasing angiotensin II generation and upregulating AT1R levels, providing insight into possible mechanisms of podocyte injury and resultant sclerosis in disease states associated with glomerular capillary hypertension.

    Article  PubMed  CAS  Google Scholar 

  42. Morton MJ, Hutchinson K, Mathieson PW, et al.: Human podocytes possess a stretch-sensitive, Ca2+-activated K+ channel: potential implications for the control of glomerular filtration. J Am Soc Nephrol 2004, 15:2981–2987.

    Article  PubMed  Google Scholar 

  43. Petermann AT, Hiromura K, Blonski M, et al.: Mechanical stress reduces podocyte proliferation in vitro. Kidney Int 2002, 61:40–50.

    Article  PubMed  CAS  Google Scholar 

  44. Petermann AT, Pippin J, Durvasula R, et al.: Mechanical stretch induces podocyte hypertrophy in vitro. Kidney Int 2005, 67:157–166.

    Article  PubMed  CAS  Google Scholar 

  45. 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, 15:1475–1487. Overexpression of the AT1R in podocytes leads to the spontaneous development of podocyte injury, proteinuria, and renal insuficiency, supporting a causal role for the chronic activation of the AT1R in the podocyte in mediating development of glomerulosclerosis.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology, University of Washington School of Medicine, Box 356521, 98195, Seattle, WA, USA

    Raghu V. Durvasula MD

Authors
  1. Raghu V. Durvasula MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stuart J. Shankland MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raghu V. Durvasula MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Durvasula, R.V., Shankland, S.J. The renin-angiotensin system in glomerular podocytes: Mediator of glomerulosclerosis and link to hypertensive nephropathy. Current Science Inc 8, 132–138 (2006). https://doi.org/10.1007/s11906-006-0009-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-006-0009-8

Keywords

Search

Navigation