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Modulation of Angiotensin II-Induced Renal Vascular Responses by PP-Fold Peptides

Dubinion, John Harvey (2006) Modulation of Angiotensin II-Induced Renal Vascular Responses by PP-Fold Peptides. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Earlier studies indicate that G₁ mediates enhanced renovascular responses to Ang II in SHR. The potentiation of Ang II by the G₁ pathway is blocked by pretreatment with pertussis toxin, an inhibitor of G₁. The G₁ pathway is also activated by receptors for PP-fold peptides; NPY, PYY, and PYY₃₋₃₆. Therefore, we hypothesize that in genetically predisposed models of hypertension PP-fold peptides augment renovascular responses to endogenous Ang II. Our study shows that LPNPY, an analogue of NPY selective for the Y₁ receptor, potentiates Ang II responses in SHR, but not WKY, kidneys in vitro. LPNPY'fs ability to potentiate Ang II renovascular responses is dependent on the Y₁ receptor and an intact G₁ pathway. The renal expression of Y₁ receptors is similar in SHR versus WKY. Our study also demonstrates that PYY₃₋₃₆, selective for the Y₂ receptor, potentiates renovascular responses to Ang II in SHR, but not WKY, in vitro. PYY₃₋₃₆ is dependent on an intact Y₂-G₁ pathway, and the Y₂ receptor is similarly expressed in the kidney of both strains. In comparing the PP-fold peptides, PYY is the most efficacious at potentiating Ang II-induced renovascular responses. Lower levels of these peptides have little effect on renal vasculature. Yet, these peptides are released with other G₁ coupled agonists, namely NE that acts on ∀₂-adrenoceptors. We observe a significant enhancement of Ang II-induced renal vasoconstriction with low level combinations of UK 14,304, an ∀₂-adrenoceptor agonist, and PYY/NPY. We demonstrate, in SHR, that nerve stimulation potentiates renal vasoconstrictive responses to Ang II. This interaction is dependent on an intact Y₁-G₁ pathway suggesting that NPY plays a predominate role in increasing renal vascular responses. PYY is a more potent agonist at augmenting renal vascular responses than is PYY₃₋₃₆. Blockade of the conversion of PYY to PYY₃₋₃₆ via a DPPIV inhibitor, P32/98, results in an increase in MABP in SHR. We also demonstrate that this effect is dependent on the Y₁ receptor pathway. This project demonstrates that PP-fold peptides may play a role in the etiology of genetic hypertension. This project is significant because it suggests a link between a high fat diet, sympathetic activation, and hypertension in a genetically susceptible animal.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dubinion, John
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFriedman, Peterpaf10@pitt.eduPAF10
Committee MemberBarchowsky, Aaronabarchowsky@eoh.pitt.eduAAB20
Committee MemberDegroat, Chetwcd2@pitt.eduWCD2
Committee MemberJackson, Edwin K.edj@pitt.eduEDJ
Committee MemberKleyman, Thomaskleyman@pitt.eduKLEYMAN
Date: 28 August 2006
Date Type: Completion
Defense Date: 28 June 2006
Approval Date: 28 August 2006
Submission Date: 23 August 2006
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: Angiotensin II; DPPIV; Gi Proteins; NE; NPY; PP-fold Peptides; PPY; Renal Pharmacology; SHR
Other ID:, etd-08232006-153035
Date Deposited: 10 Nov 2011 20:01
Last Modified: 15 Nov 2016 13:49


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