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

• Published in: Life sciences (1973) Vol. 80; no. 22; pp. 2067 - 2075
• Main Authors: Wang, Yan, Ji, Huai-Xue, Xing, Shu-Hua, Pei, Dong-Sheng, Guan, Qiu-Hua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 08.05.2007
• Subjects: Animals; Anthracenes - pharmacology; Apoptosis; Apoptosis - drug effects; c-Jun; Disease Models, Animal; Fas/FasL; JNK; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; Kidney - enzymology; Kidney - pathology; Kidney Diseases - drug therapy; Kidney Diseases - enzymology; Kidney Diseases - pathology; Necrosis - metabolism; Protective Agents - pharmacology; Rats; Rats, Sprague-Dawley; Renal ischemia/reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - enzymology; Reperfusion Injury - pathology; Signal Transduction - drug effects; Signal Transduction - physiology; SP600125; Fas/FasL; Renal ischemia/reperfusion; c-Jun; JNK; SP600125; Apoptosis
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2007.03.010

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.