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.

  • Review Article
  • Published:

Reversal of proteinuric renal disease and the emerging role of endothelin

Nature Clinical Practice Nephrology volume 4, pages 490–501 (2008)Cite this article

Abstract

Proteinuria is a major long-term clinical consequence of diabetes and hypertension, conditions that lead to progressive loss of functional renal tissue and, ultimately, end-stage renal disease. Proteinuria is also a strong predictor of cardiovascular events. Convincing preclinical and clinical evidence exists that proteinuria and the underlying glomerulosclerosis are reversible processes. This Review outlines the mechanisms involved in the development of glomerulosclerosis—particularly those responsible for podocyte injury—with an emphasis on the potential capacity of endothelin receptor blockade to reverse this process. There is strong evidence that endothelin-1, a peptide with growth-promoting and vasoconstricting properties, has a central role in the pathogenesis of proteinuria and glomerulosclerosis, which is mediated via activation of the ETA receptor. Several antiproteinuric drugs, including angiotensin-converting-enzyme inhibitors, angiotensin receptor antagonists, statins and certain calcium channel blockers, inhibit the formation of endothelin-1. Preclinical studies have demonstrated that endothelin receptor antagonists can reverse proteinuric renal disease and glomerulosclerosis, and preliminary studies in humans with renal disease have shown that these drugs have remarkable antiproteinuric effects that are additive to those of standard antiproteinuric therapy. Additional clinical studies are needed.

Key Points

  • Podocytes are gatekeepers of the glomerular filtration barrier, and podocyte injury is a prerequisite for development of proteinuria and glomerulosclerosis

  • Endothelin is a potent growth factor and vasoconstrictor, which is highly expressed in the renal vasculature and parenchyma

  • Endothelin disrupts the actin cytoskeleton of podocytes—which is necessary for the structural support and signaling of these cells—and also causes podocyte loss and nephrin shedding

  • Glomerular disease is associated with activation of renal endothelin production and can be prevented or even reversed by endothelin ETA receptor antagonists

  • Preliminary clinical studies indicate that endothelin antagonists can reverse proteinuric renal disease even when superimposed onto standard antiproteinuric therapy

  • Carefully designed, prospective clinical studies of endothelin antagonism in renal disease are required, and should take into account the receptor selectivity and potential toxicity of the drugs and the comorbidities and disease severity of the patients

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Proposed interactions between the glomerular basement membrane, glomerular endothelial cells, podocytes and slit diaphragm (based on a concept proposed by Kalluri20), showing signaling pathways via which endothelin-1 might contribute to glomerular injury.
Figure 2: Factors contributing to glomerulosclerosis and proteinuria via activation of endothelin synthesis.
Figure 3: Effects of endothelin blockade on podocyte injury in vitro.23
Figure 4: Proposed concept of renal disease regression after inhibition of endothelin.
Figure 5: Reversal of established focal segmental glomerulosclerosis in aged rats following pharmacological blockade of endothelin ETA receptors.23

Similar content being viewed by others

References

  1. Remuzzi G et al. (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116: 288–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jaber BL and Madias NE (2005) Progression of chronic kidney disease: can it be prevented or arrested? Am J Med 118: 1323–1330

    Article  PubMed  Google Scholar 

  3. de Borst MH et al. (2008) Primer: strategies for identifying genes involved in renal disease. Nat Clin Pract Nephrol 4: 265–276

    Article  PubMed  Google Scholar 

  4. Collins AJ et al. (2005) Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. Am J Kidney Dis 45 (1 Suppl 1): A5–A7, S1–S280

    Article  PubMed  Google Scholar 

  5. Xue JL et al. (2001) Forecast of the number of patients with end-stage renal disease in the United States to the year 2010. J Am Soc Nephrol 12: 2753–2758

    CAS  PubMed  Google Scholar 

  6. Eijkelkamp WB et al. (2007) Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol 18: 1540–1546

    Article  CAS  PubMed  Google Scholar 

  7. Fogo AB (2001) Progression and potential regression of glomerulosclerosis. Kidney Int 59: 804–819

    Article  CAS  PubMed  Google Scholar 

  8. Fogo AB (2005) New capillary growth: a contributor to regression of sclerosis? Curr Opin Nephrol Hypertens 14: 201–203

    Article  PubMed  Google Scholar 

  9. Fogo AB (2006) Progression versus regression of chronic kidney disease. Nephrol Dial Transplant 21: 281–284

    Article  PubMed  Google Scholar 

  10. Dussaule JC and Chatziantoniou C (2007) Reversal of renal disease: is it enough to inhibit the action of angiotensin II? Cell Death Differ 14: 1343–1349

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Reiser J et al. (2004) Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem 279: 34827–34832

    Article  CAS  PubMed  Google Scholar 

  13. Floege J et al. (1997) Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease. Kidney Int 51: 230–243

    Article  CAS  PubMed  Google Scholar 

  14. Opocensky M et al. (2006) Late-onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension 48: 965–971

    Article  CAS  PubMed  Google Scholar 

  15. Nagase M et al. (2006) Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension 47: 1084–1093

    Article  CAS  PubMed  Google Scholar 

  16. Shibata S et al. (2006) Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling. J Am Soc Nephrol 17: 754–764

    Article  CAS  PubMed  Google Scholar 

  17. Shibata S et al. (2007) Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension 49: 355–364

    Article  CAS  PubMed  Google Scholar 

  18. Asanuma K and Mundel P (2003) The role of podocytes in glomerular pathobiology. Clinical Exp Nephrol 7: 255–259

    Article  CAS  Google Scholar 

  19. Ziyadeh FN and Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4: 39–45

    Article  CAS  PubMed  Google Scholar 

  20. Kalluri R (2006) Proteinuria with and without renal glomerular podocyte effacement. J Am Soc Nephrol 17: 2383–2389

    Article  PubMed  Google Scholar 

  21. Mahan JD et al. (1986) Glomerular basement membrane anionic charge site changes early in aminonucleoside nephrosis. Am J Pathol 125: 393–401

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Rastaldi MP et al. (2006) Glomerular podocytes contain neuron-like functional synaptic vesicles. FASEB J 20: 976–978

    Article  CAS  PubMed  Google Scholar 

  23. Ortmann J et al. (2004) Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension 44: 974–981

    Article  CAS  PubMed  Google Scholar 

  24. Mundel P (2003) Urinary podocytes: lost and found alive. Kidney Int 64: 1529–1530

    Article  PubMed  Google Scholar 

  25. Petermann A and Floege J (2007) Podocyte damage resulting in podocyturia: a potential diagnostic marker to assess glomerular disease activity. Nephron Clin Pract 106: c61–c66

    Article  PubMed  Google Scholar 

  26. Kim YH et al. (2001) Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int 60: 957–968

    Article  CAS  PubMed  Google Scholar 

  27. Macconi D et al. (2006) Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention. Am J Pathol 168: 1073–1085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gross ML et al. (2003) ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy. Diabetologia 46: 856–868

    Article  CAS  PubMed  Google Scholar 

  29. Gagliardini E et al. (2007) Effect of a selective ETA receptor antagonist on podocyte function and permselective properties of the glomerular barrier in experimental diabetes. Presented at the 10th International Conference on Endothelin: 2007 Bergamo, September 16–19, Bergamo, Italy

  30. Smoyer WE et al. (1997) Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am J Physiol 273: F150–F157

    CAS  PubMed  Google Scholar 

  31. Shankland SJ et al. (2007) Podocytes in culture: past, present, and future. Kidney Int 72: 26–36

    Article  CAS  PubMed  Google Scholar 

  32. Yuan H et al. (2002) Podocyte slit-diaphragm protein nephrin is linked to the actin cytoskeleton. Am J Physiology Renal Physiol 282: F585–F591

    Article  CAS  Google Scholar 

  33. Gubler MC (2003) Podocyte differentiation and hereditary proteinuria/nephrotic syndromes. J Am Soc Nephrol 14 (Suppl 1): S22–S26

    Article  PubMed  Google Scholar 

  34. Endlich N et al. (2001) Podocytes respond to mechanical stress in vitro. J Am Soc Nephrol 12: 413–422

    CAS  PubMed  Google Scholar 

  35. Takeda T et al. (2001) Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton. J Clin Invest 108: 289–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Benigni A et al. (2004) Changes in glomerular perm-selectivity induced by angiotensin II imply podocyte dysfunction and slit diaphragm protein rearrangement. Semin Nephrol 24: 131–140

    Article  CAS  PubMed  Google Scholar 

  37. Furchgott RF and Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 299: 373–376

    Article  Google Scholar 

  38. Yanagisawa M et al. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411–415

    Article  CAS  PubMed  Google Scholar 

  39. Barton M and Yanagisawa M : Endothelin—twenty years from discovery to therapy. Can J Physiol Pharmacol, in press

  40. Rubanyi GM and Polokoff M (1994) Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46: 325–415

    CAS  PubMed  Google Scholar 

  41. Ge Y et al. (2006) Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. Am J Physiol Renal Physiol 291: F1274–F1280

    Article  CAS  PubMed  Google Scholar 

  42. Luscher TF and Barton M (2000) Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102: 2434–2440

    Article  CAS  PubMed  Google Scholar 

  43. Kohan DE (2006) The renal medullary endothelin system in control of sodium and water excretion and systemic blood pressure. Curr Opin Nephrol Hypertens 15: 34–40

    Article  CAS  PubMed  Google Scholar 

  44. Benigni A et al. (1993) A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 44: 440–444

    Article  CAS  PubMed  Google Scholar 

  45. Hocher B et al. (1997) Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99: 1380–1389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barton M et al. (2000) Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and glomerulosclerosis. J Am Soc Nephrol 11: 835–845

    CAS  PubMed  Google Scholar 

  47. Vernerová Z et al. (2008) Late-onset endothelin receptor blockade in hypertensive heterozygous REN-2 transgenic rats. Vascul Pharmacol 48: 165–173

    Article  PubMed  CAS  Google Scholar 

  48. Boffa JJ et al. (2001) Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension 37: 490–496

    Article  CAS  PubMed  Google Scholar 

  49. Benigni A et al. (1998) Unselective inhibition of endothelin receptors reduces renal dysfunction in experimental diabetes. Diabetes 47: 450–456

    Article  CAS  PubMed  Google Scholar 

  50. Gross ML et al. (2003) Renal damage in the SHR/N-cp type 2 diabetes model: comparison of an angiotensin-converting enzyme inhibitor and endothelin receptor blocker. Lab Invest 83: 1267–1277

    Article  CAS  PubMed  Google Scholar 

  51. Benigni A and Remuzzi G (2001) How renal cytokines and growth factors contribute to renal disease progression. Am J Kidney Dis 37: S21–S24

    Article  CAS  PubMed  Google Scholar 

  52. Gutierrez S et al. (1996) Endothelin-1 induces loss of proteoglycans and enhances fibronectin and collagen production in cultured rabbit synovial cells. Eur J Pharmacol 302: 191–197

    Article  CAS  PubMed  Google Scholar 

  53. Chang JM et al. (2007) Effects of endothelin-1 on thymidine uptake and fibronectin production of diabetic glomeruli. Nephrology (Carlton) 12: 62–66

    Article  CAS  Google Scholar 

  54. Morigi M et al. (2006) Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol 169: 1965–1975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Morigi M et al. (2005) In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol 166: 1309–1320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nett PC et al. (2006) Recent developments on endothelin antagonists as immunomodulatory drugs—from infection to transplantation medicine. Recent Patents Cardiovasc Drug Discov 1: 265–276

    Article  CAS  Google Scholar 

  57. Lattmann T et al. (2005) Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: role of endothelin receptor signaling. Am J Transplant 5: 1042–1049

    Article  CAS  PubMed  Google Scholar 

  58. Sasser JM et al. (2007) Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism. J Am Soc Nephrol 18: 143–154

    Article  CAS  PubMed  Google Scholar 

  59. Xia HJ et al. (2006) Up-regulated inflammatory factors endothelin, NFkappaB, TNFalpha and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats. Life Sci 79: 1812–1819

    Article  CAS  PubMed  Google Scholar 

  60. Gomez-Garre D et al. (1996) An orally active ETA/ETB receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis. Kidney Int 50: 962–972

    Article  CAS  PubMed  Google Scholar 

  61. Kawaguchi H et al. (1990) Endothelin stimulates angiotensin I to angiotensin II conversion in cultured pulmonary artery endothelial cells. J Mol Cell Cardiol 22: 839–842

    Article  CAS  PubMed  Google Scholar 

  62. Barton M et al. (2000) Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin. Hypertension 35: 329–336

    Article  CAS  PubMed  Google Scholar 

  63. Barton M et al. (1997) Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activity in vivo: role of ETA receptors for endothelin regulation. Biochem Biophys Res Commun 238: 861–865

    Article  CAS  PubMed  Google Scholar 

  64. Rebibou JM et al. (1992) Functional endothelin 1 receptors on human glomerular podocytes and mesangial cells. Nephrol Dial Transplant 7: 288–292

    Article  CAS  PubMed  Google Scholar 

  65. Jia J et al. (2008) Angiotensin II infusion induces nephrin expression changes and podocyte apoptosis. Am J Nephrol 28: 500–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zoja C et al. (1999) Protein overload activates proximal tubular cells to release vasoactive and inflammatory mediators. Exp Nephrol 7: 420–428

    Article  CAS  PubMed  Google Scholar 

  67. Wesson DE et al. (2007) Dietary protein induces endothelin-mediated kidney injury through enhanced intrinsic acid production. Kidney Int 71: 210–217

    Article  CAS  PubMed  Google Scholar 

  68. Liang XB et al. (2006) Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial cell growth. J Am Soc Nephrol 17: 1886–1895

    Article  CAS  PubMed  Google Scholar 

  69. Benigni A et al. (2004) The potential of endothelin antagonism as a therapeutic approach. Expert Opin Investig Drugs 13: 1419–1435

    Article  CAS  PubMed  Google Scholar 

  70. Gross ML and Amann K (2004) Progression of renal disease: new insights into risk factors and pathomechanisms. Curr Opin Nephrol Hypertens 13: 307–312

    Article  PubMed  Google Scholar 

  71. Zanatta CM et al. (2008) Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 80: 299–304

    Article  CAS  PubMed  Google Scholar 

  72. Chen HC et al. (2001) Plasma and urinary endothelin-1 in focal segmental glomerulosclerosis. J Clin Lab Anal 15: 59–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Susztak K et al. (2006) Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55: 225–233

    Article  CAS  PubMed  Google Scholar 

  74. Zhou X et al. (1995) High glucose alters actin assembly in glomerular mesangial and epithelial cells. Lab Invest 73: 372–383

    CAS  PubMed  Google Scholar 

  75. Petermann AT et al. (2003) Podocytes that detach in experimental membranous nephropathy are viable. Kidney Int 64: 1222–1231

    Article  PubMed  Google Scholar 

  76. Collino F et al. (2008) Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. Am J Physiol. Renal Physiol 294: F1185–F1194

    Article  CAS  PubMed  Google Scholar 

  77. Chen HM et al. (2006) Podocyte lesions in patients with obesity-related glomerulopathy. Am J Kidney Dis 48: 772–779

    Article  PubMed  Google Scholar 

  78. Saraheimo M et al. (2008) Serum adiponectin and progression of diabetic nephropathy in patients with type 1 diabetes. Diabetes Care 31: 1165–1169

    Article  CAS  PubMed  Google Scholar 

  79. Sharma K et al. (2008) Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 188: 1645–1656

    Google Scholar 

  80. Barton M et al. (2003) Obesity-associated activation of angiotensin and endothelin in the cardiovascular system. Int J Biochem Cell Biol 35: 826–837

    Article  CAS  PubMed  Google Scholar 

  81. Bedi D et al. (2006) Endothelin-1 inhibits adiponectin secretion through a phosphatidylinositol 4,5-bisphosphate/actin-dependent mechanism. Biochem Biophys Res Commun 345: 332–339

    Article  CAS  PubMed  Google Scholar 

  82. Juan CC et al. (2004) Insulin infusion induces endothelin-1-dependent hypertension in rats. Am J Physiol Endocrinol Metab 287: E948–E954

    Article  CAS  PubMed  Google Scholar 

  83. Yang Z and Li JC (2008) Stimulation of endothelin-1 gene expression by insulin via phosphoinositide-3 kinase-glycogen synthase kinase-3beta signaling in endothelial cells. Life Sci 82: 512–518

    Article  CAS  PubMed  Google Scholar 

  84. Idris I et al. (2001) Tissue- and time-dependent effects of endothelin-1 on insulin-stimulated glucose uptake. Biochem Pharmacol 62: 1705–1708

    Article  CAS  PubMed  Google Scholar 

  85. Aaltonen P et al. (2001) Changes in the expression of nephrin gene and protein in experimental diabetic nephropathy. Lab Invest 81: 1185–1190

    Article  CAS  PubMed  Google Scholar 

  86. Ortmann J et al. (2005) Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes: evidence for endothelin release by pancreatic islet beta-cells. Biochem Biophys Res Commun 334: 689–695

    Article  CAS  PubMed  Google Scholar 

  87. Mauer SM et al. (1974) Pancreatic islet transplantation. Effects on the glomerular lesions of experimental diabetes in the rat. Diabetes 23: 748–753

    Article  CAS  PubMed  Google Scholar 

  88. Lee CS et al. (1974) Renal transplantation in diabetes mellitus in rats. J Exp Med 139: 793–800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Abouna GM et al. (1983) Reversal of diabetic nephropathy in human cadaveric kidneys after transplantation into non-diabetic recipients. Lancet 2: 1274–1276

    Article  CAS  PubMed  Google Scholar 

  90. Fioretto P et al. (1998) Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339: 69–75

    Article  CAS  PubMed  Google Scholar 

  91. Marinides GN et al. (1990) Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy. Kidney Int 37: 749–757

    Article  CAS  PubMed  Google Scholar 

  92. Zoja C et al. (1992) Renal protective effect of angiotensin-converting enzyme inhibition in aging rats. Am J Med 92: 60S–63S

    Article  CAS  PubMed  Google Scholar 

  93. Remuzzi A et al. (2006) ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease. Kidney Int 69: 1124–1130

    Article  CAS  PubMed  Google Scholar 

  94. Fujita T et al. (2007) Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin–angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney Int 72: 1543–1549

    Article  CAS  PubMed  Google Scholar 

  95. Ikoma M et al. (1991) Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions. Kidney Int 40: 195–202

    Article  CAS  PubMed  Google Scholar 

  96. Ostendorf T et al. (1999) VEGF(165) mediates glomerular endothelial repair. J Clin Invest 104: 913–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ding SS et al. (2003) Chronic endothelin receptor blockade prevents both early hyperfiltration and late overt diabetic nephropathy in the rat. J Cardiovasc Pharmacol 42: 48–54

    Article  CAS  PubMed  Google Scholar 

  98. Hocher B et al. (2001) Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 87: 161–169

    Article  CAS  PubMed  Google Scholar 

  99. Kelly DJ et al. (2000) Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat. Kidney Int 57: 1882–1894

    Article  CAS  PubMed  Google Scholar 

  100. Schiffrin EL (1999) State-of-the-Art lecture. Role of endothelin-1 in hypertension. Hypertension 34: 876–881

    Article  CAS  PubMed  Google Scholar 

  101. Placier S et al. (2006) Reversal of renal lesions following interruption of nitric oxide synthesis inhibition in transgenic mice. Nephrol Dial Transplant 21: 881–888

    Article  CAS  PubMed  Google Scholar 

  102. Barton M et al. (1998) ETA receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy and endothelial dysfunction in salt-sensitive hypertension. Hypertension 31: 499–504

    Article  CAS  PubMed  Google Scholar 

  103. Honing MLH et al. (2000) ABT-627, a selective ETA-receptor anatagonist, reduces proteinuria in patients with diabetes mellitus. In: Regulation of Vascular Tone in Humans by Endothelium-derived Mediators [thesis] Utrecht: Elinkwijk BV

    Google Scholar 

  104. Wenzel RR et al. (2005) The ETA-selective antagonist SPP301 on top of standard treatment reduces urinary albumin excretion rate in patients with diabetic nephropathy [abstract F-FC093]. Presented at ASN Renal Week: 2005 November 8–13, Philadelphia, PA, USA

  105. Mann. J et al. (2006) Avosentan, a selective endothelin receptor antagonist, decreases albuminuria in patients with diabetic nephropathy. [http://www.associationhq.com/isn/forefronts/pages/ abstractview.php?id=2&page=0] (accessed 5 June 2008)

  106. Viberti G (online 2008) SPP301 (Avosentan) ASCEND clinical results. [http://www.speedel.com/assets/2008_SPP301ASCENDStudy.pdf] (accessed 5 June 2008)

  107. ClinicalTrials.gov (online 2005) [http://clinicaltrials.gov/ct2/show/NCT00120328?term=NCT00120328&rank=1] (accessed 5 June 2008)

  108. Barton M et al. (2006) Role of endothelin receptors for renal protection and survival in hypertension: waiting for clinical trials. Hypertension 48: 834–837

    Article  CAS  PubMed  Google Scholar 

  109. Black HR et al. (2007) Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study. J Clin Hypertens (Greenwich) 9: 760–769

    Article  CAS  Google Scholar 

  110. Hernandez-Perera O et al. (1998) Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 101: 2711–2719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Whaley-Connell A et al. (2008) Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment. Hypertension 51: 474–480

    Article  CAS  PubMed  Google Scholar 

  112. Eyre J et al. (2007) Statin-sensitive endocytosis of albumin by glomerular podocytes. Am J Physiol Renal Physiol 292: F674–F681

    Article  CAS  PubMed  Google Scholar 

  113. Danesh FR et al. (2002) 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy. Proc Natl Acad Sci USA 99: 8301–8305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Whaley-Connell A et al. (2008) Insulin resistance, oxidative stress, and podocyte injury: role of rosuvastatin modulation of filtration barrier injury. Am J Nephrol 28: 67–75

    Article  CAS  PubMed  Google Scholar 

  115. Gianella A et al. (2007) Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. Am J Pathol 170: 1165–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Aldigier JC et al. (2005) Regression of existing glomerulosclerosis by inhibition of aldosterone. J Am Soc Nephrol 16: 3306–3314

    Article  CAS  PubMed  Google Scholar 

  117. Zeng ZP et al. (1992) Endothelin stimulates aldosterone secretion in vitro from normal adrenocortical tissue, but not adenoma tissue, in primary aldosteronism. J Clin Endocrinol Metab 74: 874–878

    Article  CAS  PubMed  Google Scholar 

  118. Rossi GP et al. (1997) Autocrine-paracrine role of endothelin-1 in the regulation of aldosterone synthase expression and intracellular Ca2+ in human adrenocortical carcinoma NCI-H295 cells. Endocrinology 138: 4421–4426

    Article  CAS  PubMed  Google Scholar 

  119. Wang S et al. (2003) Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int 63: 2037–2049

    Article  CAS  PubMed  Google Scholar 

  120. Zeisberg M et al. (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9: 964–968

    Article  CAS  PubMed  Google Scholar 

  121. Kitten AM et al. (1997) Osteogenic protein-1 downregulates endothelin A receptors in primary rat osteoblasts. Am J Physiol 272: E967–E975

    CAS  PubMed  Google Scholar 

  122. De Petris L et al. (2007) Bone morphogenetic protein-7 delays podocyte injury due to high glucose. Nephrol Dial Transplant 22: 3442–3450

    Article  CAS  PubMed  Google Scholar 

  123. Mitu GM et al. (2007) BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am Journal Physiol 293: F1641–F1648

    CAS  Google Scholar 

  124. Ueda H et al. (2008) BMP in podocytes is essential for normal glomerular capillary formation. J Am Soc Nephrol 19: 685–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Parving HH et al. (2008) Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358: 2433–2446

    Article  CAS  PubMed  Google Scholar 

  126. Benigni A and Remuzzi G (1998) Novel strategies to retard renal disease progression: combining ACE inhibition with endothelin receptor blocking? Nephrol Dial Transplant 13: 2734–2738

    Article  CAS  PubMed  Google Scholar 

  127. Harman C (2007) What new drugs can nephrologists look forward to in the next year or two? Nat Clin Pract Nephrol 3: 235

    Article  PubMed  Google Scholar 

  128. Orisio S et al. (2007) The SNP5333 gene polymorphism of endothelin A receptor is independently associated with increased albuminuria in type 2 diabetes. Presented at the 10th International Conference on Endothelin: 2007 Bergamo, September 16–19, Bergamo, Italy

Download references

Acknowledgements

I thank all present and former collaborators and colleagues who have contributed to the studies discussed in this manuscript, particularly Sidney Shaw, Pierre Moreau, Livius d'Uscio, Philipp Nett, Elvira Haas, Matthias Kretzler, Thomas Lattmann, and Kerstin Amann (who also provided me with the electron microscopy photographs presented in this manuscript). I am indebted to Ariela Benigni for critical reading of the manuscript and many valuable suggestions. I apologize to investigators whose work was not cited because of space limitations. This article was supported by the Swiss National Science Foundation and the University of Zürich. Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Author information

Author notes

  1. Klinik und Poliklinik für Innere Medizin, Departement für Innere Medizin, Universitätsspital Zürich, Rämistrasse 100, CH-8091 Zürich, Switzerland barton@usz.ch

Authors and Affiliations

  1. M Barton is Professor and Attending Physician in the Department of Internal Medicine at the Klinik und Poliklinik für Innere Medizin, Universitätsspital Zürich, Zürich, Switzerland.,

    Matthias Barton

Authors
  1. Matthias Barton
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Supplementary Figure 1

Effect of endothelin blockade on podocyte injury in vivo in a rat model of age-dependent focal segmental glomerulosclerosis. (PDF 97 kb)

Supplementary Figure 2

Effects of endothelin blockade on glomerulosclerosis and proteinuria in vivo in a rat model of age-dependent focal segmental glomerulosclerosis. (PDF 73 kb)

Supplementary Table 1

Summary of clinical and preclinical studies demonstrating functional and/or structural reversal of proteinuric renal disease with various pharmacologic and nonpharmacologic interventions, excluding endothelin receptor antagonists. (DOC 125 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barton, M. Reversal of proteinuric renal disease and the emerging role of endothelin. Nat Rev Nephrol 4, 490–501 (2008). https://doi.org/10.1038/ncpneph0891

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0891

This article is cited by

Search

Advanced 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