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Peroxisome Proliferator-Activated Receptor / Exerts a Strong Protection from Ischemic Acute Renal Failure

Emmanuel Letavernier^*, Joëlle Perez^*, Elisabeth Joye, Agnès Bellocq^*, Bruno Fouqueray^*, Jean-Philippe Haymann^*, Didier Heudes, Walter Wahli, Béatrice Desvergne and Laurent Baud^*

^* INSERM U489, Tenon Hospital, Paris, France; Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, Lausanne-Dorigny, Switzerland; and INSERM U430, Cordeliers Institute, Paris, France

Address correspondence to: Dr. Laurent Baud, INSERM U489, Hôpital Tenon, 4 rue de la Chine, Paris, France 75020. Phone: 33-1-5601-7951; Fax: 33-1-5601-7003; E-mail: laurent.baud{at}tnn.ap-hop-paris.fr

Received for publication September 28, 2004. Accepted for publication May 3, 2005.

Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor / (PPAR/) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPAR/ could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPAR/^+/– and PPAR/^–/– mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPAR/ ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na⁺. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPAR/ ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPAR/ as a remarkable new target for preconditioning strategies.

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