PPAR-alpha ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G.

Abstract

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 (PPAR-alpha) 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 proapoptotic renal endonuclease G (Endo G) were increased compared with saline-treated mice. In situ hybridization and immunohistochemical 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. Pretreatment of PPAR-alpha wild-type mice with PPAR-alpha 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. Morphological examination of tubular injury in the PPAR-alpha wild-type mice that received PPAR-alpha 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 PPAR-alpha-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 PPAR-alpha ligand protects against cisplatin-induced renal injury via a PPAR-alpha-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.

• Authors: Shenyang Li, A Basnakian, Renu Bhatt, Judit Megyesi, Neriman Gokden, Sudhir V Shah, Didier Portilla
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 287 Issue 5 Pg. F990-8 (Nov 2004) ISSN: 1931-857X [Print] United States
• PMID: 15280156 (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

• Ligands
• Protein Synthesis Inhibitors
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• Endodeoxyribonucleases
• endonuclease G
• Cisplatin

Topics

• Acute Kidney Injury (prevention & control)
• Animals
• Blotting, Western
• Cell Death (drug effects)
• Cisplatin (antagonists & inhibitors, toxicity)
• Endodeoxyribonucleases (biosynthesis, genetics)
• Gene Expression Regulation, Enzymologic (drug effects)
• Immunohistochemistry
• In Situ Hybridization
• Kidney (drug effects, enzymology)
• Kidney Tubules, Proximal (drug effects, enzymology)
• Ligands
• Male
• Mice
• Protein Synthesis Inhibitors (toxicity)
• RNA, Messenger (biosynthesis, genetics)
• Receptors, Cytoplasmic and Nuclear
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (pharmacology)