Angiotensin II induces cell growth and IL-6 mRNA expression through the JAK2-STAT3 pathway in rat cerebellar astrocytes

Abstract

The pleiotrophic effects of angiotensin II (Ang II) play important roles in astrocyte growth and inflammatory responses. We investigated whether Ang II induces astrocyte growth and interleukin-6 (IL-6) mRNA expression in rat cerebellar astrocytes through Janus kinase 2-signal transduction activator of transcription (JAK2-STAT3). Ang II increased JAK2 and STAT3 phosphorylation in a time- and a dose-dependent manner. One hundred nanomolar Ang II induced maximal phosphorylation of both JAK2 and STAT3 between 15 min and 30 min. The Ang II-mediated phosphorylation of both JAK2 and STAT3 was blocked by AG490, a selective JAK2 inhibitor. Losartan, a selective AT1 receptor antagonist, inhibited Ang II-mediated JAK2 and STAT3 phosphorylation, while pretreatment with an AT2 receptor blocker, PD123319, was ineffective. Ang II increased the mRNA expression of IL-6 in a concentration-and time-dependent manner. Maximal IL-6 mRNA expression occurred with 100 nM Ang II, and the peak effect occurred in a biphasic manner at 3 h and between 12 and 24 h. Moreover, pretreatments with AG490 attenuated Ang II-induced IL-6 mRNA levels, and Ang II-induced astrocyte growth. This study has demonstrated that Ang II induced the phosphorylation of both JAK2 and STAT3 via the AT1 receptor in cerebellar astrocytes. In addition, our results suggest that JAK2 and STAT3 are upstream signals that mediate Ang II-induced IL-6 mRNA expression and astrocyte growth. These findings represent a novel non-classical mechanism of Ang II signaling in cerebellar astrocytes.