Autoregulation is an intrinsic property of the preglomerular microvasculature that begins to fail within 6 days of Ang II hypertension resulting in increased transmission of arterial pressure to the glomerulus. Chronic elevation of glomerular capillary pressure is a major risk factor for hypertensive renal injury. The mechanisms responsible for the decline in pressure-mediated autoregulatory vasoconstriction in Ang II hypertension remain unclear. P2X1 receptors are critically important in mediating afferent arteriolar autoregulatory behavior. P2X1 receptor inactivation impairs autoregulatory responses. Ang II hypertension blunts autoregulation by 50% and impairs P2X1 receptor-mediated vasoconstriction and Ca2+ signaling responses. Ang II hypertension, and P2Y12 receptor activation, contribute to inflammation and fibrosis and converge on a loss of autoregulatory efficiency. Clopidogrel selectively blocks ADP sensitive P2Y12 receptors and reduces renal fibrosis without decreasing blood pressure. Clopidogrel also inhibits expression of MCP-1, TGF-?, fibronectin, and PAI-1, all of which are associated with renal injury. Therefore, this competing renewal application will address the central hypothesis that inflammatory processes involving P2Y12 receptor activation contribute to impairment of P2X1 receptor-mediated afferent arteriolar vasoconstriction, impairment of renal autoregulatory control and leads to renal injury in Ang-II-dependent hypertension. Studies will establish the impact of P2Y12 receptor blockade on impaired autoregulation in Ang-II hypertension, afferent arteriolar responsiveness to P2 receptor stimulation and activation of intrarenal inflammatory mediators.
Specific aim 1 will test the hypothesis that P2Y12 receptor-dependent inflammatory processes contribute to the decline in autoregulatory control observed in Ang II hypertension.
Specific aim 2 will test the hypothesis that P2Y12 receptor-dependent mechanisms contribute to impairment of afferent arteriolar responses to P2 receptor activation resulting in impaired afferent arteriolar autoregulatory behavior.
Specific aim 3 will test the hypothesis that P2Y12 receptors stimulate expression of inflammatory mediators that impair renal microvascular reactivity, leading to autoregulatory dysfunction and renal injury. These studies will provide new information on the role of P2Y12 receptors and inflammation on P2 receptor- mediated regulation of renal microvascular function, autoregulatory behavior and the relationship between P2X1 receptor activation and Ang-II hypertensive renal injury.

Public Health Relevance

Hypertensive renal injury is a growing problem in western cultures. Much of the injury relates to pressure- related impairment of renal vascular function. This application will address the mechanisms responsible for hypertension-induced impairment of renal vascular function and its relationship to hypertensive kidney damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK044628-18
Application #
8247828
Study Section
Special Emphasis Panel (ZRG1-CVS-B (02))
Program Officer
Ketchum, Christian J
Project Start
1994-08-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
18
Fiscal Year
2012
Total Cost
$306,158
Indirect Cost
$97,887
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Kohan, Donald E; Rossi, Noreen F; Inscho, Edward W et al. (2011) Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 91:1-77
Guan, Zhengrong; Inscho, Edward W (2011) Role of adenosine 5'-triphosphate in regulating renal microvascular function and in hypertension. Hypertension 58:333-40
Guan, Zhengrong; Inscho, Edward W (2011) Endothelin and the renal vasculature. Contrib Nephrol 172:35-49
Inscho, Edward W; Cook, Anthony K; Clarke, Andrea et al. (2011) P2X1 receptor-mediated vasoconstriction of afferent arterioles in angiotensin II-infused hypertensive rats fed a high-salt diet. Hypertension 57:780-7
Giachini, Fernanca R C; Osmond, David A; Zhang, Shali et al. (2010) Clopidogrel, independent of the vascular P2Y12 receptor, improves arterial function in small mesenteric arteries from AngII-hypertensive rats. Clin Sci (Lond) 118:463-71
Inscho, Edward W (2009) Lewis K. Dahl Memorial Lecture. Mysteries of renal autoregulation. Hypertension 53:299-306
Inscho, Edward W (2009) ATP, P2 receptors and the renal microcirculation. Purinergic Signal 5:447-60
Fuller, Andrew J; Hauschild, Benjamin C; Gonzalez-Villalobos, Romer et al. (2005) Calcium and chloride channel activation by angiotensin II-AT1 receptors in preglomerular vascular smooth muscle cells. Am J Physiol Renal Physiol 289:F760-7
Inscho, E W (2001) P2 receptors in regulation of renal microvascular function. Am J Physiol Renal Physiol 280:F927-44