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ligand protects during cisplatin induced acute renal failure by preventing inhibition of renal FAO and PDC activity
1 Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
2 Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA
3 Department of Pathology, Duke University, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: portilladidier{at}uams.edu.
Previous studies demonstrated that during cisplatin-induced acute renal failure there is a significant reduction in proximal tubule fatty acid oxidation. We now report on the
effects of PPAR
ligand Wy-14,643(WY) on the abnormalities of medium chain fatty acid oxidation and Pyruvate Dehydrogenase Complex (PDC) activity in kidney tissue of cisplatin-treated mice. Cisplatin causes a significant reduction of mRNA levels and enzyme activity of mitochondrial Medium Chain Acyl CoA Dehydrogenase (MCAD).
PPAR ligand Wy-14643 ameliorated cisplatin-induced acute renal failure and prevented cisplatin induced reduction of mRNA levels and enzyme activity of MCAD. In contrast, in cisplatin treated PPAR null mice, Wy-14,643 did not protect kidney function and did not reverse cisplatin induced decreased expression of MCAD. Cisplatin inhibited renal Pyruvate Dehydrogenase Complex activity prior to the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPARagonist Wy-14,643. Cisplatin also induced increased mRNA and protein levels of Pyruvate Dehydrogenase Kinase-4 (PDK4), and PPAR ligand Wy-14643 prevented cisplatin induced increased expression of PDK4 protein levels in wild type mice. We conclude that PPAR agonists have therapeutic potential for cisplatin induced acute renal failure. Use of PPAR ligands prevent acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes MCAD mediated fatty acid oxidation and PDC activity.
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