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1 Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China; Center of Pediatric Nephrology, Nanjing Medical University, Najing, China
2 Center of Pediatric Nephrology, Nanjing Medical University, Najing, China
3 Department of Medical Oncology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, China
4 Division of Nephrology, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, USA
* To whom correspondence should be addressed. E-mail: tianxin.yang{at}hsc.utah.edu.
Angiotensin II (Ang II) has been shown to activate c-Jun NH2-terminal kinase (JNK) in cultured mesangial cells but the functional implication of this phenomenon remains to be determined, largely due to the lack of an effective approach to block JNK. Therefore, the present study was carried out to examine whether JNK is involved in Ang II-induced cell proliferation in cultured human mesangial cells (HMCs) with the use of a newly developed JNK-selective blocker SP600125. Within minutes, treatment with 100 nM Ang II activated all three members of MAP kinases family, including extracellular signal-regulated protein kinase (Erk) 1/2, JNK, and p38 in cultured HMCs, as assessed by immunoblotting detection of phosphorylation of MAP kinases. Ang II-dependent activation of JNK was further confirmed by detection of increased phosphorylation and transcription activity of c-Jun following the Ang II treatment. SP600125 at 5-10 µM range almost completely abolished the activation of JNK by Ang II without affecting the activities of Erk1/2 and p38. Following treatment with 100 ng Ang II, there was a steady increase in 3H-thymidine incorporation that was blocked by SP60025 in a dose and time-dependent manner. Similarly, SP600125 dose-dependently reduced Ang II-induced increase in cell number. The anti-proliferative effect of SP60025 was further determined by cell cycle analysis with flow cytometry. Twenty four hours following Ang II treatment, 50% of the quiescent HMCs (G0/G1) progressed into the S phase and the cell cycle progression was almost completely prevented in the presence of SP60025. Our data suggests that JNK mediates the proliferative effect of Ang II in cultured HMCs and thus represents a novel therapeutic target for treatment of chronic renal diseases.
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