Type of Document	Dissertation
Author	Andresen, Bradley T.
Author's Email Address	bradley_andresen@hotmail.com
URN	etd-06022002-180949
Title	Angiotensin II Signaling to Phospholipase D in a Model of Genetic Hypertension
Degree	Doctor of Philosophy
Program	Molecular Pharmacology
School	School of Medicine
Advisory Committee	Advisor Name Title Peter A. Friedman, Ph.D. Committee Chair Daniel L. Altschuler, Ph.D Committee Member Edwin K. Jackson, Ph.D. Committee Member Gregg E. Homanics, Ph.D. Committee Member Guillermo G. Romero, Ph.D. Committee Member Matthew F. Muldoon, M.D., M.P.H. Committee Member
Keywords	Rho A Angiotensin II receptor type 2 Angiotenisn II receptor type 1 Angiotenisn II Phospholipase D Hypertension Spontaneously Hypertensive Rat
Date of Defense	2002-06-04
Availability	restricted
Abstract In spontaneously hypertensive rats (SHR) the hypersensitivity of the renal vasculature to angiotensin II (Ang II), compared to Wistar-Kyoto rats (WKY), appears to be the determining factor in the development and progression of hypertension. Recent evidence indicates that the ERK cascade and NAD(P)H oxidase generation of superoxide are involved in smooth muscle contraction, and Phospholipase D (PLD) generation of phosphatidic acid is involved in activation of ERK and NAD(P)H. Importantly, Ang II-mediated PLD activity is greater in aortic smooth muscle from SHR compared with WKY; however, this signaling pathway has not been examined in the kidney vasculature. The purpose of these studies were to define Ang II-mediated signal transduction mechanism(s) involved in PLD regulation in WKY and SHR preglomerular smooth muscle cells (PGSMCs). The goals of this study were to determine: 1) whether Ang II-mediated PLD activity is greater in SHR; 2) the Ang II signaling pathway(s) responsible for regulating PLD activity, and whether they are altered in SHR; and 3) whether PLD-mediated generation of phosphatidic acid is involved in Ang II-induced activation of the ERK cascade. The data indicates that the mechanisms leading to activation of PLD are similar in WKY and SHR and PLD is required for Ang II activation of ERK; however, Ang II more potently activates PLD in SHR. Further analysis indicates that the AT2 receptor inhibits AT1 receptor/RhoA-dependent activation of PLD through a nitric oxide/cGMP-dependent phosphorylation of RhoA at serine 188, which promotes RhoGDI inhibition of RhoA. These experiments expose two key differences between WKY and SHR PGSMCs: 1) SHR have an increased AT1/AT2 receptor ratio; and 2) SHR are less sensitive to nitric oxide and cGMP. Therefore, the hypersensitivity of the SHR to Ang II may be due to an imbalance in Ang II receptors and/or impaired AT2 receptor-mediated signaling within the kidney vasculature.
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