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Published ahead of print on September 24, 2009
J Am Soc Nephrol 20: 2412-2425, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008080868
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BASIC RESEARCH

Dexamethasone Ameliorates Renal Ischemia-Reperfusion Injury

Sanjeev Kumar*, David A. Allen*, Julius E. Kieswich*, Nimesh S. A. Patel*, Steven Harwood*, Emanuela Mazzon{dagger}, Salvatore Cuzzocrea{dagger}, Martin J. Raftery*, Christoph Thiemermann* and Muhammad M. Yaqoob*

*Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom; and
{dagger}Department of Clinical and Experimental Medicine and Pharmacology, Institute of Pharmacology, University of Messina, and IRCCS Centro Neurolesi "Bonino-Pulejo," Messina, Italy

Correspondence: Dr. Sanjeev Kumar, Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary, University of London, Charter House Square, Barbican, London EC1M 6BQ, United Kingdom. Phone: 0044-207-882-2122; Fax: 0044-207-882-8252; E-mail: drksanjeev{at}yahoo.com

Received for publication August 19, 2008. Accepted for publication July 6, 2009.

In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemia-reperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.






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