Dubinion, John Harvey
(2006)
Modulation of Angiotensin II-Induced Renal Vascular Responses by PP-Fold Peptides.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| 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: |
http://etd.library.pitt.edu/ETD/available/etd-08232006-153035/, etd-08232006-153035 |
| Date Deposited: |
10 Nov 2011 20:01 |
| Last Modified: |
15 Nov 2016 13:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9246 |
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