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Endothelin and endothelin antagonists in chronic kidney disease.

Kohan DE, Barton M - Kidney Int. (2014)

Bottom Line: The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020.Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident.Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

ABSTRACT
The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.

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Ultrastructural and histological images demonstrating short-term effects of ERA treatment (darusentan) on aging-associated FSGS in the rat. a, Untreated kidney with FSGS, transmission electron microscopy of a podocyte (P) demonstrating hypertrophy of the glomerular basement membrane (GBM) and podocyte injury indicated by diffuse foot process effacement, podocyte hypertrophy, and autophagy-dependent vacuolar degeneration (arrow). b, Kidney with FSGS after 4 weeks of ERA treatment: ERA therapy caused regression of GBM hypertrophy and disappearance of podocyte vacuolization (arrow). c, light microscopy image (hematoxylin/eosin) of a glomerulus in an untreated kidney with FSGS, showing podocyte hypertrophy with enlarged nuclei, prominent nucleoles, and vacuolar degeneration, as well as hypertrophy of glomerular capillaries and matrix deposition/fibrosis (purple). d, Kidney with FSGS, ERA-treated for 4 weeks, showing normalization of podocyte size, virtually complete disappearance of vacuolar degeneration (arrows), as well as regression of glomerular capillary hypertrophy and matrix deposition. In this study (21), ERA treatment for 4 weeks induced regression of glomerulosclerosis by 55% and a 57% reduction in proteinuria. Panels adapted (21) and reproduced with permission of the publisher. Scale bar, 10 μm (c, d)
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Figure 2: Ultrastructural and histological images demonstrating short-term effects of ERA treatment (darusentan) on aging-associated FSGS in the rat. a, Untreated kidney with FSGS, transmission electron microscopy of a podocyte (P) demonstrating hypertrophy of the glomerular basement membrane (GBM) and podocyte injury indicated by diffuse foot process effacement, podocyte hypertrophy, and autophagy-dependent vacuolar degeneration (arrow). b, Kidney with FSGS after 4 weeks of ERA treatment: ERA therapy caused regression of GBM hypertrophy and disappearance of podocyte vacuolization (arrow). c, light microscopy image (hematoxylin/eosin) of a glomerulus in an untreated kidney with FSGS, showing podocyte hypertrophy with enlarged nuclei, prominent nucleoles, and vacuolar degeneration, as well as hypertrophy of glomerular capillaries and matrix deposition/fibrosis (purple). d, Kidney with FSGS, ERA-treated for 4 weeks, showing normalization of podocyte size, virtually complete disappearance of vacuolar degeneration (arrows), as well as regression of glomerular capillary hypertrophy and matrix deposition. In this study (21), ERA treatment for 4 weeks induced regression of glomerulosclerosis by 55% and a 57% reduction in proteinuria. Panels adapted (21) and reproduced with permission of the publisher. Scale bar, 10 μm (c, d)

Mentions: Focal segmental glomerulosclerosis is a widely varying clinicopathological entity characterized by injury to the glomerular filtration barrier (19). Urinary excretion of ET-1 is increased in primary FSGS patients and glomerular ET-1 expression is enhanced in experimental FSGS (45). Podocyte-specific mechanisms have been proposed as underlying FSGS development (46, 47). In humans and rodents, aging is associated with spontaneous development of FSGS (46), the susceptibility for which has recently been linked to autophagy-related mechanisms controlling podocyte vacuolization. Aging-associated FSGS is associated with increased renal ET-1 expression (48, 49). Studies in rodents with aging-FSGS demonstrated that ETA-selective antagonism for 1 month caused blood pressure-independent regression of FSGS, proteinuria and GBM hypertrophy, partially restored podocyte morphology, and reduced podocyte autophagy (21) (Figure 2). Of note, ERA treatment markedly down-regulated p21waf1/cip1, a cell cycle inhibitor and inhibitor of cell growth that contributes to CKD progression in FSGS animals (21, 50, 51).


Endothelin and endothelin antagonists in chronic kidney disease.

Kohan DE, Barton M - Kidney Int. (2014)

Ultrastructural and histological images demonstrating short-term effects of ERA treatment (darusentan) on aging-associated FSGS in the rat. a, Untreated kidney with FSGS, transmission electron microscopy of a podocyte (P) demonstrating hypertrophy of the glomerular basement membrane (GBM) and podocyte injury indicated by diffuse foot process effacement, podocyte hypertrophy, and autophagy-dependent vacuolar degeneration (arrow). b, Kidney with FSGS after 4 weeks of ERA treatment: ERA therapy caused regression of GBM hypertrophy and disappearance of podocyte vacuolization (arrow). c, light microscopy image (hematoxylin/eosin) of a glomerulus in an untreated kidney with FSGS, showing podocyte hypertrophy with enlarged nuclei, prominent nucleoles, and vacuolar degeneration, as well as hypertrophy of glomerular capillaries and matrix deposition/fibrosis (purple). d, Kidney with FSGS, ERA-treated for 4 weeks, showing normalization of podocyte size, virtually complete disappearance of vacuolar degeneration (arrows), as well as regression of glomerular capillary hypertrophy and matrix deposition. In this study (21), ERA treatment for 4 weeks induced regression of glomerulosclerosis by 55% and a 57% reduction in proteinuria. Panels adapted (21) and reproduced with permission of the publisher. Scale bar, 10 μm (c, d)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4216619&req=5

Figure 2: Ultrastructural and histological images demonstrating short-term effects of ERA treatment (darusentan) on aging-associated FSGS in the rat. a, Untreated kidney with FSGS, transmission electron microscopy of a podocyte (P) demonstrating hypertrophy of the glomerular basement membrane (GBM) and podocyte injury indicated by diffuse foot process effacement, podocyte hypertrophy, and autophagy-dependent vacuolar degeneration (arrow). b, Kidney with FSGS after 4 weeks of ERA treatment: ERA therapy caused regression of GBM hypertrophy and disappearance of podocyte vacuolization (arrow). c, light microscopy image (hematoxylin/eosin) of a glomerulus in an untreated kidney with FSGS, showing podocyte hypertrophy with enlarged nuclei, prominent nucleoles, and vacuolar degeneration, as well as hypertrophy of glomerular capillaries and matrix deposition/fibrosis (purple). d, Kidney with FSGS, ERA-treated for 4 weeks, showing normalization of podocyte size, virtually complete disappearance of vacuolar degeneration (arrows), as well as regression of glomerular capillary hypertrophy and matrix deposition. In this study (21), ERA treatment for 4 weeks induced regression of glomerulosclerosis by 55% and a 57% reduction in proteinuria. Panels adapted (21) and reproduced with permission of the publisher. Scale bar, 10 μm (c, d)
Mentions: Focal segmental glomerulosclerosis is a widely varying clinicopathological entity characterized by injury to the glomerular filtration barrier (19). Urinary excretion of ET-1 is increased in primary FSGS patients and glomerular ET-1 expression is enhanced in experimental FSGS (45). Podocyte-specific mechanisms have been proposed as underlying FSGS development (46, 47). In humans and rodents, aging is associated with spontaneous development of FSGS (46), the susceptibility for which has recently been linked to autophagy-related mechanisms controlling podocyte vacuolization. Aging-associated FSGS is associated with increased renal ET-1 expression (48, 49). Studies in rodents with aging-FSGS demonstrated that ETA-selective antagonism for 1 month caused blood pressure-independent regression of FSGS, proteinuria and GBM hypertrophy, partially restored podocyte morphology, and reduced podocyte autophagy (21) (Figure 2). Of note, ERA treatment markedly down-regulated p21waf1/cip1, a cell cycle inhibitor and inhibitor of cell growth that contributes to CKD progression in FSGS animals (21, 50, 51).

Bottom Line: The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020.Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident.Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

ABSTRACT
The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.

Show MeSH
Related in: MedlinePlus