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Am J Physiol Renal Physiol (July 27, 2004). doi:10.1152/ajprenal.00206.2004
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Submitted on June 3, 2004
Accepted on July 23, 2004

PPARalpha ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of Renal Endonuclease G

Shenyang Li1, Renu Bhatt1, Judit Megyesi1, Neriman Gokden1, Sudhir V Shah1, and Didier Portilla1*

1 Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA

* To whom correspondence should be addressed. E-mail: portilladidier{at}uams.edu.

Cisplatin injury to the kidney is characterized in part by inhibition of substrate oxidation, inflammation, and tubular cell death in the form of apoptosis and necrosis. Recently we demonstrated that cisplatin-induced inhibition of substrate oxidation can be reversed by the administration of Peroxisome Proliferator Activated Receptor-alpha (PPARalpha) ligands, resulting in amelioration of renal function. We therefore hypothesize that by improving fatty acid oxidation in vivo might protect renal function by reducing both apoptosis and necrosis in cisplatin-treated mice. Mice subjected to a single intraperitoneal injection of cisplatin developed acute renal failure (ARF) at days 3 and 4. At day 4 after cisplatin injection mRNA, protein levels, and enzyme activity of pro-apoptotic renal Endonuclease G (Endo G) were increased when compared to saline treated mice. In situ hybridization and immuno-histochemical studies localized the increased expression of Endo G mRNA to the cytosolic compartment and Endo G protein to the nuclear compartment of proximal tubules in cisplatin-treated mice. Pre-treatment of PPARalpha wild type mice with PPARalpha ligand WY-14643 reduced significantly cisplatin-induced increased protein expression and enzyme activity of Endo G, and prevented the nuclear translocation of mitochondrial Endo G. Morphologic examination of tubular injury in the PPARalpha wild type mice that received PPARalpha ligand and cisplatin did show significant amelioration of acute tubular necrosis, as well as a significant reduction in the number of apoptotic cells in the proximal tubule when compared with the cisplatin-treated group. In contrast, in PPARalpha null mice treated with the ligand and cisplatin, Endo G protein expression was not reduced and this was accompanied by lack of protection of kidney function. We conclude that PPARalpha ligand protects against cisplatin-induced renal injury via a PPARalpha-dependent mechanism by reducing the expression and enzyme activity of proximal tubule Endo G, which results in amelioration of both proximal tubule cell apoptosis and necrosis.




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