Angiotensin II induces proliferation of cultured rat astrocytes through c-Jun N-terminal kinase

Previously we showed that tyrosine kinases and ERK1/2 mediate angiotensin II (Ang II)-induced cellular proliferation in astrocytes. In the current study, we investigated whether Ang II activates c-Jun N-terminal kinase (JNK) and determined if JNK mediates Ang II-induced astrocyte growth in cultured brainstem astrocytes. Ang II activated JNK in a time- and concentration-dependent manner. Maximal stimulation of 14-fold over basal occurred with 100 nM Ang II and was significantly apparent 5 min after treatment. Ang II-induced JNK phosphorylation was abolished by co-treatment with the AT1 receptor antagonist, losartan, but not by PD123319 (an AT2 receptor antagonist). The JNK inhibitor, SP600125 (10 μM), markedly inhibited Ang II-induced JNK phosphorylation (by 84%) and astrocyte proliferation (by over 90%). Pretreatment of astrocytes with 10 μM PP2 (Src inhibitor) inhibited Ang II stimulation of JNK (by 90%) whereas, the protein kinase C (PKC) inhibitor, Go6976, failed to inhibit Ang II-mediated JNK phosphorylation. In conclusion, we showed for the first time that JNK mediates Ang II-specific astrocyte proliferation. In addition, Ang II activation of the JNK pathway is mediated by Src and not through PKC activation. This study is the first to show that JNK mediates Ang II effects in astrocytes and may provide a better understanding of the functions of Ang II in astrocytes from brainstem in particular and of glial cells in general.