Role of the JAK2/STAT3 Pathway in Angiotensin II Signaling in Rat Astrocytes

Grant Winners

Dean

Abstract

Angiotensin II (Ang II) is a biologically active octapeptide that triggers a myriad of physiological responses that may lead to hypertension, congestive heart failure and other cardiovascular diseases. In the brain Ang II triggers increased sympathetic outflow and other responses, implicated in physiological as well as pathological consequences of the peptide. However, studies delineating the pathways that govern Ang II effects in the brain are limited. The Janus kinase-signal transducer and activator of transcription (JAK2/STAT3) pathway is a key player in Ang II physiological and pathological responses in peripheral cells mediating the production of the inflammatory cytokine, interleukin-6, and angiotensinogen, key molecules that are involved in physiological and pathological effects of Ang II. However, the role of the JAK2/STAT3 pathway in Ang II effects in the brain is unknown. Thus in the present project, we propose to investigate the role of the JAK2/STAT3 pathway in mediating Ang II effects in the central nervous system using cultured rat astrocytes as a model brain cell system. Astrocytes will be used since they have the necessary components to synthesize Ang II and in fact are the major source of angiotensinogen, the precursor molecule for Ang II in the brain. In this proposal we will: a) determine whether Ang II activates the JAK2/STAT3 pathway in astrocytes and b) investigate whether the JAK2/STAT3 pathway mediates Ang II activation of angiotensinogen and interleukin-6 expression in astrocytes. The proposed studies are critical in enhancing our understanding of the pathways that govern Ang II effects in the brain and will provide molecular clues for designing novel or adjunct therapies in the clinical management of cardiovascular diseases.