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Angiotensin II Signaling to Phospholipase D in a Model of Genetic Hypertension

Andresen, Bradley T. (2002) Angiotensin II Signaling to Phospholipase D in a Model of Genetic Hypertension. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Andresen, Bradley T.bradley_andresen@hotmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFriedman, Peter A.friedman@server.pharm.pitt.edu
Committee MemberAltschuler, Daniel L.altschul@server.pharm.pitt.edu
Committee MemberJackson, Edwin K.edj@pitt.eduEDJ
Committee MemberHomanics, Gregg E.homanicsge@anes.upmc.edu
Committee MemberRomero, Guillermo G.ggr@pitt.eduGGR
Committee MemberMuldoon, Matthew F.mfm10@pitt.eduMFM10
Date: 26 September 2002
Date Type: Completion
Defense Date: 4 June 2002
Approval Date: 26 September 2002
Submission Date: 2 June 2002
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Angiotenisn II; Angiotenisn II receptor type 1; Angiotensin II receptor type 2; Hypertension; Rho A; Phospholipase D; Spontaneously Hypertensive Rat
Other ID: http://etd.library.pitt.edu:80/ETD/available/etd-06022002-180949/, etd-06022002-180949
Date Deposited: 10 Nov 2011 19:46
Last Modified: 15 Nov 2016 13:44
URI: http://d-scholarship.pitt.edu/id/eprint/7990

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