c-Jun NH2-terminal kinase mediation of angiotensin II-induced proliferation of human mesangial cells.
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, SP-600125. Within minutes, treatment with 100 nM ANG II activated all three members of MAP kinase 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 after the ANG II treatment. SP-600125 ranging from 5 to 10 microM almost completely abolished the activation of JNK by ANG II without affecting the activities of Erk1/2 and p38. After treatment with 100 ng ANG II, there was a steady increase in [3H]thymidine incorporation that was blocked by SP-60025 in a dose- and time-dependent manner. Similarly, SP-600125 dose dependently reduced the ANG II-induced increase in cell number. The antiproliferative effect of SP-60025 was further determined by cell-cycle analysis with flow cytometry. Twenty-four hours after 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 SP-60025. Our data suggest 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.
Zhang
Aihua
A
Department of Nephrology, Nanjing Children's Hospital, China.
Ding
Guixia
G
Huang
Songming
S
Wu
Yuanjun
Y
Pan
Xiaoqing
X
Guan
Xiaoxiang
X
Chen
Ronghua
R
Yang
Tianxin
T
D000804:Angiotensin II / Q000494:pharmacology*; D000873:Anthracenes / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000873:Anthracenes; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases