Our results during the last funding period indicate that activation of renovascular Y1 receptors (Y1Rs) dramatically enhances renovascular responses to physiological levels of angiotensin II (Ang II) in kidneys of spontaneously hypertensive rats (SHR). However, Y1Rs have little effect on Ang ll-induced responses in kidneys of normotensive Wistar-Kyoto rats (WKY). In stark contrast, activation of Y2 receptors (Y2Rs) has, at most, only a minor effect on renovascular responses to Ang II in SHR kidneys, with no effect whatsoever in WKY kidneys. These data indicate that endogenous agonists of Y1 Rs, but not Y2Rs, would potentiate Ang ll-induced renal vasoconstriction in genetically-susceptible kidneys, provided these endogenous agonists could reach the renal microcirculation. Are there endogenous agonists of Y1 Rs that could activate Y1Rs in the kidney microcirculation? The answer is yes. A fatty meal releases peptide YY1-36 (PYY1-36) into the systemic circulation from endocrine L-cells in the small bowel, colon and rectum producing physiologically active levels of PYY1-36 in plasma that are 500% to 1000% above basal circulating levels, and this circulating PYY1-36 would be delivered promptly to the renal microcirculation via the blood stream (humoral input to kidney microcirculation). Renal sympathetic nerves release neuropeptide Y1-36 (NPY1- 36) in response to CNS-mediated activation of renal sympathetic nerves (neural input to kidney microcirculation), resulting in high local levels of NPY1-36 in sympathetically-innervated renal microvessels during renal sympathetic activation. Because both PYY1-36 and NPY1-36 are potent Y1R agonists, physiological processes that increase PYY1-36 release from the gut, NPY1-36 release from renal sympathetic nerves or both simultaneously would activate Y1Rs in the renal microcirculation, which in genetically-susceptible kidneys would enhance Ang ll-induced renal vasoconstriction. It is conceivable, however, that stimulation of Y1Rs by physiological processes that increase the exposure of the renal microcirculation to PYY1-36 and NPY1-36 is diminished by the activity of vascular dipeptidyl peptidase IV (DPP IV) residing in the walls of blood vessels that comprise the renal microcirculation. DPP IV converts PYY1-36 to PYY3-36 and NPY1-36 to NPY3-36 by cleaving two amino acids from the N-terminus of either PYY1-36 or NPY1-36. Whereas PYY1-36 and NPY1-36 are potent Y1R agonists, PYY3-36 and NPY3-36 are inactive at Y1Rs but are potent and selective Y2R agonists. These facts suggest the hypothesis that DPP IV in the renal vasculature is a critical determinant of the extent to which PYY1-36 and NPY1-36 enhance renovascular responses to Ang II in genetically-susceptible kidneys. The testing of this hypothesis is the focus of this application. The proposed hypothesis is absolutely novel. The concept that DPP IV exists in the renal vasculature and regulates renal blood flow has never been proposed or tested.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069846-08
Application #
7787042
Study Section
Special Emphasis Panel (ZRG1-CVS-N (02))
Program Officer
Thrasher, Terry N
Project Start
2002-05-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$371,250
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jackson, Edwin K; Mi, Zaichuan (2017) 8-Aminoguanosine Exerts Diuretic, Natriuretic, and Glucosuric Activity via Conversion to 8-Aminoguanine, Yet Has Direct Antikaliuretic Effects. J Pharmacol Exp Ther 363:358-366
Jackson, Edwin K; Zhang, Yumeng; Cheng, Dongmei (2017) Alkaline Phosphatase Inhibitors Attenuate Renovascular Responses to Norepinephrine. Hypertension 69:484-493
Jackson, Edwin K; Zhang, Yumeng; Gillespie, Delbert D et al. (2017) SDF-1? (Stromal Cell-Derived Factor 1?) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen. J Am Heart Assoc 6:
Jackson, Edwin K; Kotermanski, Shawn E; Menshikova, Elizabeth V et al. (2017) Adenosine production by brain cells. J Neurochem 141:676-693
Schaufelberger, Sara A; Rosselli, Marinella; Barchiesi, Federica et al. (2016) 2-Methoxyestradiol, an endogenous 17?-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism. Am J Physiol Endocrinol Metab 310:E313-22
Jackson, Edwin K; Menshikova, Elizabeth V; Mi, Zaichuan et al. (2016) Renal 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion. J Am Soc Nephrol 27:2069-81
Jackson, Edwin K; Boison, Detlev; Schwarzschild, Michael A et al. (2016) Purines: forgotten mediators in traumatic brain injury. J Neurochem 137:142-53
Jackson, Edwin K; Gillespie, Delbert G; Mi, Zaichuan (2016) 8-Aminoguanosine and 8-Aminoguanine Exert Diuretic, Natriuretic, Glucosuric, and Antihypertensive Activity. J Pharmacol Exp Ther 359:420-435
Tofovic, Stevan P; Salah, Eman M; Smits, Glenn J et al. (2016) Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction. J Pharmacol Exp Ther 356:333-40
Dubey, Raghvendra K; Fingerle, J├╝rgen; Gillespie, Delbert G et al. (2015) Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D. Hypertension 66:1207-19

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