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SP600125, a selective JNK inhibitor, protects ischemic renal injury via suppressing the extrinsic pathways of apoptosis.

Abstract
Accumulating evidence suggests that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in renal ischemia/reperfusion injury. However, the downstream mechanism that accounts for the proapoptotic actions of JNK during renal ischemia/reperfusion has not been elucidated. We report that SP600125, a potent, cell-permeable, selective, and reversible inhibitor of c-Jun N-terminal kinase (JNK), potently decreased renal epithelial tubular cell apoptosis induced by renal ischemia/reperfusion via suppression of the extrinsic pathway. This corresponds to the decrease in JNK phosphorylation at 20 min and c-Jun phosphorylation (Ser63/73) at 3 h after renal ischemia. Additionally, SP600125 attenuated the increased expression of FasL induced by ischemia/reperfusion at 3 h. The administration of SP600125 prior to ischemia was also protective. Thus, our findings imply that SP600125 can inhibit the activation of the JNK-c-Jun-FasL pathway and protect renal tubular epithelial cells against ischemia/reperfusion-induced apoptosis. Taken together, these results indicate that targeting the JNK pathway provides a promising therapeutic approach for renal ischemia/reperfusion injury.
AuthorsYan Wang, Huai-Xue Ji, Shu-Hua Xing, Dong-Sheng Pei, Qiu-Hua Guan
JournalLife sciences (Life Sci) Vol. 80 Issue 22 Pg. 2067-75 (May 08 2007) ISSN: 0024-3205 [Print] Netherlands
PMID17459422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anthracenes
  • Protective Agents
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
Topics
  • Animals
  • Anthracenes (pharmacology)
  • Apoptosis (drug effects)
  • Disease Models, Animal
  • JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • Kidney (enzymology, pathology)
  • Kidney Diseases (drug therapy, enzymology, pathology)
  • Necrosis (metabolism)
  • Protective Agents (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury (drug therapy, enzymology, pathology)
  • Signal Transduction (drug effects, physiology)

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