Submitted on August 2, 2007
Accepted on June 12, 2008
Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia/reperfusion injury
Ewen M Harrison1*, Eva Sharpe1, Christopher O Bellamy2, Stephen J McNally1, Luke Devey1, O James Garden1, James A. Ross1, and Stephen J Wigmore1
1 Tissue Injury and Repair Group, University of Edinburgh, Edinburgh, United Kingdom
2 Department of Pathology, University of Edinburgh, United States
* To whom correspondence should be addressed. E-mail: mail{at}ewenharrison.com.
Heat shock proteins (Hsps) are protective in models of transplantation, yet practical strategies to up-regulate them remain elusive. The heat shock protein-90 binding agent (HBA) geldanamycin and its analogues (17-AAG and 17-DMAG) are known to up-regulate Hsps and confer cellular protection but have not been examined in a model relevant to transplantation. We examined the ability of HBAs to up-regulate Hsp expression and confer protection in renal adenocarcinoma (ACHN) cells in vitro and in a mouse model of kidney ischemia/reperfusion injury. Hsp70 gene expression was increased 30 - 40-times in ACHN cells treated with HBAs and trimerisation and DNA-binding of HSF1 was demonstrated. A 3 fold and 2 fold increase in Hsp70 and Hsp27 protein expression, respectively, was found in ACHNs treated with HBAs. HBAs protected ACHN cells from an H2O2-mediated oxidative stress and HSF1 siRNA was found to abrogate HBA-mediated Hsp induction and protection. In vivo, Hsp70 was up-regulated in the kidney, liver, lungs and heart of HBA-treated mice. This was associated with a functional and morphological renal protection from ischemia/reperfusion (I/R) injury. Therefore, HBAs mediate up-regulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury.
