Endothelin Antagonists in Diabetic Nephropathy

Abstract

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...

Association between Endothelin-1 Levels and Kidney Disease among Blacks

“…There is ongoing research attempting to improve the risk-benefit ratio for therapeutic agents targeting the endothelin pathway to delay kidney disease progression. 26 Our study findings add to the substantial mechanistic evidence from basic science research and clinical trials on the endothelin pathway and kidney disease.…”

Endothelin

“…This deletion resulted in less albuminuria and protection from glomerulosclerosis and podocyte loss ( Lenoir et al, 2014 ). These results suggest that in mice at least, the ET B receptor may play as important a role as does the ET A receptor in diabetes, whereas previous studies have suggested the latter was the main subtype mediation the deleterious actions of ET-1 ( Chandrashekar and Juncos, 2014 ).…”

What is damaging the kidney in lupus nephritis?

“…ACE inhibitors also reduce endothelial activation by increasing NO production independently of their anti-hypertensive effects (76). Podocytes lacking both endothelin receptors are protected from damage in animal models of diabetes and an endothelin antagonist reduced proteinuria in patients with diabetic nephropathy (156). Targeting of VEGF-A (157) or PDGF has proved more challenging because the relationships between angiogenesis, inflammation and fibrosis are still not fully understood.…”