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
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Podocytes are gatekeepers of the glomerular filtration barrier, and podocyte injury is a prerequisite for development of proteinuria and glomerulosclerosis
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Endothelin is a potent growth factor and vasoconstrictor, which is highly expressed in the renal vasculature and parenchyma
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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
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Glomerular disease is associated with activation of renal endothelin production and can be prevented or even reversed by endothelin ETA receptor antagonists
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Preliminary clinical studies indicate that endothelin antagonists can reverse proteinuric renal disease even when superimposed onto standard antiproteinuric therapy
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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
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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.
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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)
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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
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DOI: https://doi.org/10.1038/ncpneph0891
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