Endothelins in the normal and diseased kidney

Abstract

Endothelin-1 (ET-1) is a 21-amino acid peptide that potently modulates renal function. ET-1 is produced by, and binds to, most renal cell types. ET-1 exerts a wide range of biologic effects in the kidney, including constriction of most renal vessels, mesangial cell contraction, inhibition of sodium and water reabsorption by the nephron, enhancement of glomerular cell proliferation, and stimulation of extracellular matrix accumulation. ET-1 functions primarily as an autocrine or paracrine factor; its renal effects must be viewed in the context of its local production and actions. This is particularly important when comparing ET-1 biology in the nephron, where it promotes relative hypotension through increased salt and water excretion, with ET-1 effects in the vasculature, where it promotes relative hypertension through vasoconstriction. Numerous studies indicate that ET-1 is involved in the pathogenesis of a broad spectrum of renal diseases. These include those characterized by excessive renal vascular resistance, such as ischemic renal failure, cyclosporine (CyA) nephrotoxicity, radiocontrast nephropathy, endotoxemia, rhabdomyolysis, acute liver rejection, and others. ET-1 appears to play a role in cell proliferation in the setting of inflammatory glomerulonephritides. The peptide also may mediate, at least in part, excessive extracellular matrix accumulation and fibrosis occurring in chronic renal failure, diabetes mellitus, and other disorders. Deranged ET1 production in the nephron may cause inappropriate sodium and water retention, thereby contributing to the development and/or maintenance of hypertension. Finally, impaired renal clearance of ET-1 may cause hypertension in patients with end-stage renal disease. Many ET-1 antagonists have been developed; however, their clinical usefulness has not yet been determined. Despite this, these agents hold great promise for the treatment of renal diseases; it is hoped that the next decade will witness their introduction into clinical practice.