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PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity.

Abstract
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 peroxisome proliferator-activated receptor-alpha (PPAR alpha) ligand Wy-14643 (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 in mRNA levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD). PPAR alpha ligand WY 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 alpha null mice, WY did not protect kidney function and did not reverse cisplatin-induced decreased expression of MCAD. Cisplatin inhibited renal PDC activity before the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPAR alpha agonist WY. Cisplatin also induced increased mRNA and protein levels of pyruvate dehydrogenase kinase-4 (PDK4), and PPAR alpha ligand WY prevented cisplatin-induced increased expression of PDK4 protein levels in wild-type mice. We conclude that PPAR alpha agonists have therapeutic potential for cisplatin-induced acute renal failure. Use of PPAR alpha ligands prevents acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes, MCAD-mediated fatty acid oxidation and PDC activity.
AuthorsShenyang Li, Pengfei Wu, Padma Yarlagadda, Nicole M Vadjunec, Alan D Proia, Robert A Harris, Didier Portilla
JournalAmerican journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 286 Issue 3 Pg. F572-80 (Mar 2004) ISSN: 1931-857X [Print] United States
PMID14612380 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Fatty Acids
  • Isoenzymes
  • Ligands
  • Pyrimidines
  • Pyruvate Dehydrogenase Complex
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • pirinixic acid
  • Acyl-CoA Dehydrogenase
  • Protein Kinases
  • pyruvate dehydrogenase kinase 4
  • Cisplatin
Topics
  • Acute Kidney Injury (chemically induced, enzymology, prevention & control)
  • Acyl-CoA Dehydrogenase (metabolism)
  • Animals
  • Body Weight (drug effects)
  • Cisplatin
  • Fatty Acids (metabolism)
  • Isoenzymes (genetics, metabolism)
  • Kidney (drug effects, enzymology, pathology)
  • Ligands
  • Male
  • Mice
  • Mice, Knockout
  • Oxidation-Reduction
  • Protein Kinases (genetics, metabolism)
  • Pyrimidines (therapeutic use)
  • Pyruvate Dehydrogenase Complex (antagonists & inhibitors, metabolism)
  • RNA, Messenger (metabolism)
  • Receptors, Cytoplasmic and Nuclear (agonists, genetics)
  • Transcription Factors (agonists, genetics)

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