Modulation of endothelin receptors in hypertension and renal pathophysiology

Endothelins (ET) are potent vasoconstrictor peptides implicated in the control of blood pressure and renal function. Three different isoforms (ET-1,2 and 3) have been identified deriving from proteolytic processing of specific prohormones. ETs acts on two distinct G-protein coupled receptors: the ETA, selective for ET-1, mediates vasoconstriction, the ETB, binding equally ET isoforms, mediates vasodilation and vasoconstriction. Both receptors are present in the heart and kidney. Intravenous infusion of ET-1 into experimental animals increases blood pressure and decreases glomerular filtration rate and renal blood flow due to afferent and efferent constriction. Whether such hemodynamic effects were mediated by ETA or ETB receptor is matter of investigation. Renal cells are capable to synthesize ET-1 and mesangial cells proliferate and produce extracellular matrix proteins when exposed to the peptide. In rats with renal mass ablation, a model characterized by systemic hypertension and progressive glomerulosclerosis, renal ET-1 and ETB receptor gene expression and urinary excretion of ET-1 progressively increase with time and correlate with proteinuria and glomerulosclerosis. Blocking ET-1ʹs biological activity by selective ETA or receptor antagonists lowers blood pressure and has a beneficial effect on renal disease progression in rats with remnant kidney, suggesting that ET receptor antagonists could be potential therapeutic tools for treatment of human progressive nephropathies.