ENDOTHELINS IN THE NORMAL AND DISEASED KIDNEY

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 ty pes. ET-1 exerts a wide range of biologic effects in the kidney, inclu ding constriction of most renal vessels, mesangial cell contraction, i nhibition of sodium and water reabsorption by the nephron, enhancement of glomerular cell proliferation, and stimulation of extracellular ma trix accumulation. ET-1 functions primarily as an autocrine or paracri ne factor; its renal effects must be viewed in the context of its loca l production and actions. This is particularly important when comparin g ET-1 biology in the nephron, where it promotes relative hypotension through increased salt and water excretion, with ET-1 effects in the v asculature, where it promotes relative hypertension through vasoconstr iction. Numerous studies indicate that ET-1 is involved in the pathoge nesis of a broad spectrum of renal diseases. These include those chara cterized by excessive renal vascular resistance, such as ischemic rena l failure, cyclosporine (CyA) nephrotoxicity, radiocontrast nephropath y, endotoxemia, rhabdomyolysis, acute liver rejection, and others, ET- 1 appears to play a role in cell proliferation in the setting of infla mmatory glomerulonephritides. The peptide also may mediate, at least i n part, excessive extracellular matrix accumulation and fibrosis occur ring in chronic renal failure, diabetes mellitus, and other disorders, Deranged ET-1 production in the nephron may cause inappropriate sodiu m 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 usefuln ess has not yet been determined, Despite this, these agents hold great promise for the treatment of renal diseases; it is hoped that the nex t decade will witness their introduction into clinical practice. (C) 1 997 by the National Kidney Foundation, Inc.