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Endothelial Dysfunction in Acute Renal Failure

Role of Circulatingand Tissue Endothelin-1

FRANK RUSCHITZKA^*, SIDNEY SHAW, DANIEL GYGI^*, GEORG NOLL^*, MATTHIAS BARTON^* and THOMAS F. LÜSCHER^*

^* Department of Cardiology, University Hospital Zürich, and Cardiovascular Research, Institute of Physiology, University of Zürich-Irchel, Switzerland.
Department of Clinical Research, Inselspital Bern, Switzerland.

Correspondence to Dr. Thomas F. Lüscher, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. Phone: +41 1 255 21 21 or 21 77; Fax: +41 1 255 42 51; E-mail: frankruschitzka{at}yahoo.com

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 ¹²⁵I-ET-1 was markedly prolonged, whereas ¹²⁵I-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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673