Angiotensin III Induces c-Jun N-terminal Kinase Leading to Proliferation of Rat Astrocytes

Objective. We determined whether Angiotensin (Ang) III induced phosphorylation of c-Jun N terminal kinase (JNK) mitogen activate protein kinases (MAPK) leading to astrocyte growth. Background. Ang III is a potent peptide with similar responses as Ang II. Studies in the brain focuses on responses observed after injection of the peptide with just a few studies focused on molecular effects of Ang III. We have shown in astrocytes that Ang III induced astrocyte proliferation and phosphorylation of ERK1/2 MAPK through the AT1 receptor. Methods. Gel electrophoresis and Western blotting techniques were used to determine Ang III JNK MAPK effects. 3H-Thymidine incorporation was used to determine astrocyte growth. Results. Ang III induced JNK phosphorylation in a concentration- and time-dependent manner. Maximal stimulation occurred with 100 nM Ang III and was apparent within a minute of peptide exposure. The JNK inhibitor, SP600125, prevented Ang III phosphorylation of JNK, as well as Ang III-mediated astrocyte growth. Losartan, the selective AT1 receptor antagonist, prevented Ang III-induced JNK phosphorylation while the AT2 receptor blocker, PD123319, was ineffective. Our findings suggest that Ang III interacts with Ang AT1 receptors to stimulate the JNK MAPK pathway leading to astrocyte growth. This study is the first to show that Ang III actions may involve the JNK MAPK pathway in astrocytes and provide key information that may lead to a better understanding of Ang III functions in the brain, in particular in astrocytes. Grants. This study was supported by a President's Faculty Research and Development Grant.