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Am J Physiol Renal Physiol 295: F741-F748, 2008. First published June 25, 2008; doi:10.1152/ajprenal.90244.2008
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{alpha}2-Adrenergic agonists protect against radiocontrast-induced nephropathy in mice

F. T. Billings, IV,1 Sean W. C. Chen,1 Mihwa Kim,1 Sang Won Park,1 Joseph H. Song,1 Shuang Wang,2 Joseph Herman,4 Vivette D'Agati,3 and H. Thomas Lee1

Departments of 1Anesthesiology, 2Biostatistics, and 3Pathology, College of Physicians and Surgeons, Columbia University, New York, New York; and 4Division of Clinical Pharmacology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Submitted 10 April 2008 ; accepted in final form 23 June 2008

Radiocontrast nephropathy (RCN) is a common clinical problem for which there is no effective therapy. Utilizing a murine model, we tested the hypothesis that {alpha}2-adrenergic receptor agonists (clonidine and dexmedetomidine) protect against RCN induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL/6 mice were pretreated with saline, clonidine, or dexmedetomidine before induction of RCN. Some mice were pretreated with yohimbine (a selective {alpha}2-receptor antagonist) before saline, clonidine, or dexmedetomidine administration. {alpha}2-Agonist-treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 h after iohexol injection. Yohimbine reversed the protective effects of clonidine and dexmedetomidine pretreatment. Injection of iohexol resulted in a rapid (~90 min) fall of renal outer medullary blood flow. Clonidine and dexmedetomidine pretreatment significantly attenuated this perfusion decrease without changing systemic blood pressure. To determine whether proximal tubular {alpha}2-adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) cells and rat pulmonary microvascular endothelial cells with iohexol after vehicle, clonidine, or dexmedetomidine pretreatment. Iohexol caused a direct dose-dependent reduction of HK-2 and rat pulmonary microvascular endothelial cell viability, but {alpha}2-agonists failed to preserve the viability of both cell types. We conclude that {alpha}2-adrenergic receptor agonists protect mice against RCN by preserving outer medullary renal blood flow. As {alpha}2-agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.

acute renal failure; iohexol; clonidine; dexmedetomidine; yohimbine; HK-2 cells; medullary ischemia


Address for reprint requests and other correspondence: H. T. Lee, Dept. of Anesthesiology, Anesthesiology Research Laboratories, Columbia Univ., P & S Box 46 (PH-5), 630 West 168thSt., New York, NY 10032-3784 (e-mail: tl128{at}columbia.edu)






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