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Am J Physiol Renal Physiol 295: F397-F405, 2008. First published June 18, 2008; doi:10.1152/ajprenal.00361.2007
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Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury

Ewen M. Harrison,1 Eva Sharpe,1 Christopher O. Bellamy,2 Stephen J. McNally,1 Luke Devey,1 O. James Garden,1 James A. Ross,1 and Stephen J. Wigmore1

1Tissue Injury and Repair Group and 2Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom

Submitted 2 August 2007 ; accepted in final form 12 June 2008

Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to upregulate them remain elusive. The heat shock protein 90-binding agent (HBA) geldanamycin and its analogs (17-AAG and 17-DMAG) are known to upregulate Hsps and confer cellular protection but have not been investigated in a model relevant to transplantation. We examined the ability of HBAs to upregulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia-reperfusion (I/R) injury. Hsp70 gene expression was increased 30-40 times in ACHN cells treated with HBAs, and trimerization and DNA binding of heat shock transcription factor-1 (HSF1) were demonstrated. A three- and twofold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHN cells treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress, and HSF1 short interfering RNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was upregulated in the kidneys, liver, lungs, and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from I/R injury. Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.

kidney transplantation; ischemia-reperfusion injury; oxidative stress; geldanamycin


Address for reprint requests and other correspondence: E. M. Harrison, Tissue Injury and Repair Group, Univ. of Edinburgh, Rm. FU501, Chancellor's Bldg., Little France Crescent, Edinburgh EH16 4SB, UK (e-mail: mail{at}ewenharrison.com)




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