Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Saleh, Mohamed A.; Pollock, Jennifer S.; Pollock, David M.

doi:10.1124/jpet.111.178988

Cited by 62 publications

(65 citation statements)

References 39 publications

(53 reference statements)

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“…A prolonged and possibly exacerbated vasoconstriction 29 after ET-B antagonism may have also helped to aggravate MV rarefaction, which may have contributed to the persistence of renal fibrosis. Therefore, because ET-A blockade had a significant hemodynamic effect on the PTRAS-treated kidney that led to recover renal function, it is possible that the combination of vasoconstriction and enhanced progrowth activity after addition of ET-B blockade may have expanded renal damage, 32,33 which may have, consequently, blunted the effect of PTRAS.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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Percutaneous transluminal renal angioplasty/stenting (PTRAS) is frequently used to treat renal artery stenosis and renovascular disease (RVD); however, renal function is restored in less than one half of the cases. This study was designed to test a novel intervention that could refine PTRAS and enhance renal recovery in RVD. Renal function was quantified in pigs after 6 weeks of chronic RVD (induced by unilateral renal artery stenosis), established renal damage, and hypertension. Pigs with RVD then underwent PTRAS and were randomized into three groups: placebo (RVD+PTRAS), chronic endothelin-A receptor (ET-A) blockade (RVD+PTRAS+ET-A), and chronic dual ET-A/B blockade (RVD+PTRAS+ET-A/B) for 4 weeks. Renal function was again evaluated after treatments, and then, ex vivo studies were performed on the stented kidney. PTRAS resolved renal stenosis, attenuated hypertension, and improved renal function but did not resolve renal microvascular rarefaction, remodeling, or renal fibrosis. ET-A blocker therapy after PTRAS significantly improved hypertension, microvascular rarefaction, and renal injury and led to greater recovery of renal function. Conversely, combined ET-A/B blockade therapy blunted the therapeutic effects of PTRAS alone or PTRAS followed by ET-A blockade. These data suggest that ET-A receptor blockade therapy could serve as a coadjuvant intervention to enhance the outcomes of PTRAS in RVD. These results also suggest that ET-B receptors are important for renal function in RVD and may contribute to recovery after PTRAS. Using clinically available compounds and techniques, our results could contribute to both refinement and design of new therapeutic strategies in chronic RVD. Chronic renovascular disease (RVD) increases the risk of cardiovascular morbidity and mortality and may progressively induce renal injury, leading to ESRD. 1 Percutaneous transluminal renal angioplasty/stenting (PTRAS) is a frequently used therapeutic strategy to treat patients with chronic RVD. Targeting the renal stenosis is a logical choice for treating RVD, because the resolution of the vascular obstruction followed by restoration of blood flow to the site of injured tissues should play an important role to initiate successful repairing responses. The use of PTRAS in RVD grew significantly during the past 20 years, 2 with tremendous progress in successfully resolving renal stenosis and restoring blood flow (.95% of the cases). 3 However, despite the high technical success of PTRAS, improvement in renal function is still observed in a relatively small portion of the cases. 4 The reasons for the persistent poor outcomes after PTRAS in RVD are still unclear. Furthermore, the dissociation between the technical success of PTRAS and renal outcomes underscores a pressing need to identify more effective therapeutic strategies in RVD.Endothelin-1 (ET-1) is a powerful renal vasoconstrictor and mitogenic peptide that plays important roles in controlling BP and renal function.

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Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Chade¹,

Tullos²,

Stewart³

et al. 2015

Journal of the American Society of Nephrology

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“…In addition to a direct adverse effect of VEGF inhibition on podocyte function and expression of slit-diaphragm proteins, ET-1 can exert negative effects on podocyte function, which, additionally to the disruption of VEGF pathway, may contribute to glomerular injury and proteinuria. 10,11,31,32 For instance, a subpressor dose of ET-1 administered to SpragueDawley rats was found to increase glomerular permeability and inflammation, as well as nephrinuria, effects that could be blocked by an endothelin receptor type A antagonist. 31 In cultured podocytes, ET-1 through activation of endothelin receptor type A induces nephrin shedding concomitant with a redistribution of the podocyte's cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

“…10,11,31,32 For instance, a subpressor dose of ET-1 administered to SpragueDawley rats was found to increase glomerular permeability and inflammation, as well as nephrinuria, effects that could be blocked by an endothelin receptor type A antagonist. 31 In cultured podocytes, ET-1 through activation of endothelin receptor type A induces nephrin shedding concomitant with a redistribution of the podocyte's cytoskeleton. 10 Recently, Buelli et al 11 have shown activation of the β-arrestin-1 signaling pathway by ET-1, resulting in transition of podocytes from an epithelial to mesenchymal cell type.…”

Section: Discussionmentioning

confidence: 99%

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

et al. 2015

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Abstract-Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only at the intermediate and high doses. Compared with vehicle circulating endothelin-1 increased dose dependently, whereas 24-hour urinary endothelin excretion decreased. Light and electron microscopy revealed glomerular endotheliosis and ischemia with the intermediate and high doses of sunitinib but completely absent histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner.We conclude that the sunitinib-induced rise in blood pressure requires lower doses than its induction of renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria, given the lack of histopathologic changes with the low dose of sunitinib. (Hypertension. 2015;66:543-549.

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“…9 Finally, several studies have shown that ET receptor antagonists ameliorate experimental diabetic nephropathy. 8,12,13 It is within this context that two papers in this issue of JASN are of special interest: an experimental study that elucidates the functional significance of the ET A and ET B receptors on podocytes in diabetic kidney injury and a complementary clinical study demonstrating the antiproteinuric effects of an ET antagonist in diabetic nephropathy.…”

mentioning

confidence: 99%

“…9 Finally, several studies have shown that ET receptor antagonists ameliorate experimental diabetic nephropathy. 8,12,13 It is within this context that two In the experimental study, Lenoir et al 14 used a novel mutant mouse wherein podocyte-specific, double deletion of the ET A and ET B receptors was induced. They not only demonstrated that these mice were protected against diabetes-induced podocyte loss and the attendant glomerulosclerosis but also provide evidence that the ET B receptor may play as important a role as does the ET A receptor; this finding challenges the widely held notion that the deleterious effects of ET in diabetes are due to activation of the ET A receptor.…”

mentioning

confidence: 99%

Endothelin Antagonists in Diabetic Nephropathy

Chandrashekar¹,

Juncos

2014

Journal of the American Society of Nephrology

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The pivotal discovery of endothelin (ET) by Yanagisawa and colleagues 1 in 1988 generated wide interest in this peptide, as evidenced by the nearly 27,000 articles published to date that have examined its role in biology. ET is now recognized as essential to the function of various organs and metabolic processes. 2 The ET family consists of three 21-amino acid peptides-ET-1 (ubiquitous and most biologically active), ET-2, and ET-3-that exert their actions via two receptor subtypes: ET A and ET B 2 . Activation of these receptors usually, but not always, incites opposing actions; an additional consideration is that the ET B receptor also acts as a clearance receptor. 3 Consequently, the effects of ET can vary among different organs depending on the amount being formed and on the receptor subtypes present. For instance, in the cardiovascular system ET induces vasoconstriction and growth via ET A receptors and vasodilation and growth inhibition via ET B receptors. 1,3 The net effect results in an increase in systemic vascular resistance and BP. This potentially injurious effect is augmented by ET's ability to stimulate growth factors and cytokines, which induce neutrophil adhesion, platelet aggregation, and formation of extracellular matrix protein. 3 Together, these actions can precipitate a vicious cycle that accelerates hypertension and atherosclerosisinduced vascular disease. 3 Despite its importance in the cardiovascular system, ET plays an even larger role in regulating renal function and injury. This is because the kidneys are exquisitely sensitive to ET-1 (up to 10-fold more than are other organs 4 ) and because the components of the ET system are widely distributed throughout the kidney; ET-1 is present in the renal microvasculature, in all types of glomerular cells, and in the tubules (the renal medulla contains the highest ET-1 levels in the body 5 ). Thus, it is no surprise that ET-1 has such a key role in regulating renal hemodynamics, salt and water homeostasis, and acid-base balance 6 and in modulating cell proliferation, extracellular matrix accumulation, inflammation, and fibrosis. 7 Consequently, any abnormality in the intrarenal ET system may result in renal dysfunction (e.g., salt sensitivity) and/or injury. Indeed, ET may participate in the progression of renal injury during obesity, hypertension, and diabetes. 7 Because most of the deleterious effects of ET-1 appear to be mediated through the ET A receptors, this receptor has become an attractive therapeutic target in various forms of cardiovascular and renal diseases, such as diabetes. 3 Diabetic nephropathy is an attractive target for ET-1 blockade because several lines of evidence implicate ET in this disease. First, the synthesis and/or effects of ET-1 are increased in response to hyperglycemia, hypertensive glomerular injury, and insulin, 8 which results in increased renal expression and systemic circulatory levels of ET-1 in experimental and clinical diabetes. 9,10 Second, abnormalities in the ET system are present in the renal areas tar...

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Distinct Actions of Endothelin A-Selective Versus Combined Endothelin A/B Receptor Antagonists in Early Diabetic Kidney Disease

Cited by 62 publications

References 39 publications

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Endothelin-A Receptor Antagonism after Renal Angioplasty Enhances Renal Recovery in Renovascular Disease

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

Endothelin Antagonists in Diabetic Nephropathy

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