Angiotensin III Regulation of Mitogen Activated Protein Kinases in Astrocytes

Grant Winner

Dean

Abstract

Angiotensin II (Ang II) is a biologically active peptide of the renin-angiotensin system (RAS) that is important in regulating fluid balance, sodium intake, thirst and blood pressure. It is known that the peripheral and central RAS contributes to blood pressure regulation. Chronic hypertension can cause organ damage leading to cardiac events and stroke contributing to more than 500,000 annual deaths in the United States. Angiotensin III (Ang III) is a biologically active metabolite of Ang II with similar effects and receptor binding properties as Ang II. It is postulated that central effects of Ang II may be indirect due to rapid conversion of Ang II to Ang III by aminopeptidase A, suggesting a role of Ang III in central RAS effects. This project will use cultured rat astrocytes as an in vitro model of a brain system to study whether Ang III activates signaling pathways that are known to be activated by Ang II in these cells. Mitogen activated protein kinases (MAP kinases) constitute three families (ERK1/2, SAPK/JNK, and P38) that are known intracellular regulators of Ang II. We have established that ERK1/2 and SAPK/JNK but not P38 mediate Ang II effects in astrocytes. Thus, the following specific aims will: (a) determine whether Ang III increases the expression of ERK1/2 MAP kinases in cultured rat astrocytes; (b) determine whether Ang III increases the expression of SAPK/JNK MAP kinases in cultured rat astrocytes; and (c) determine whether Ang III increases the growth of cultured rat astrocytes. Studies will determine the receptors involved in Ang III effects, as well as determine whether Ang II must be converted to Ang III to turn on ERK1/2 and SAPK/JNK MAP kinases as well as to initiate astrocyte growth. In most cases the underlying cause of hypertension is not known; therefore, it is important that we understand how different types of cells are affected by peptides generated by the RAS system to allow us to design better drugs for the prevention and treatment of hypertension and other diseases associated with the RAS.