Endothelial Dysfunction in Acute Renal Failure

Abstract. The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats ( n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twentyfour hours after clamp release, contractions to angiotensin I (AngI) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET A and Et B receptor mRNA expression was determined. Sham-operated animals served as controls ( n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased ( P < 0.01). Plasma half-life of radiolabeled 125 I-ET-1 was markedly prolonged, whereas 125 I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted ( P < 0.05) and those to KC1 were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF ( P < 0.05 to 0.001). Correspondingly, ET A and Et B receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery ( r = -0.827, P < 0.001) and the aorta ( r = -0.812, P < 0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET A and Et B receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.