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
Guan, Zhengrong; Singletary, Sean T; Cha, Haword et al. (2016) Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats. Am J Physiol Renal Physiol 310:F456-65
Guan, Zhengrong; VanBeusecum, Justin P; Inscho, Edward W (2015) Endothelin and the renal microcirculation. Semin Nephrol 35:145-55
Fellner, Robert C; Guan, Zhengrong; Cook, Anthony K et al. (2015) Endothelin contributes to blunted renal autoregulation observed with a high-salt diet. Am J Physiol Renal Physiol 309:F687-96
Van Beusecum, Justin; Inscho, Edward W (2015) Regulation of renal function and blood pressure control by P2 purinoceptors in the kidney. Curr Opin Pharmacol 21:82-8
Pandit, Meghana M; Inscho, Edward W; Zhang, Shali et al. (2015) Flow regulation of endothelin-1 production in the inner medullary collecting duct. Am J Physiol Renal Physiol 308:F541-52
Osmond, David A; Zhang, Shali; Pollock, Jennifer S et al. (2014) Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. Am J Physiol Renal Physiol 306:F619-28
Fellner, Robert C; Cook, Anthony K; O'Connor, Paul M et al. (2014) High-salt diet blunts renal autoregulation by a reactive oxygen species-dependent mechanism. Am J Physiol Renal Physiol 307:F33-40
Giachini, Fernanda R; Leite, Romulo; Osmond, David A et al. (2014) Anti-platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats. PLoS One 9:e91890
Guan, Zhengrong; Fellner, Robert C; Van Beusecum, Justin et al. (2014) P2 receptors in renal autoregulation. Curr Vasc Pharmacol 12:818-28
Guan, Zhengrong; Singletary, Sean T; Cook, Anthony K et al. (2014) Sphingosine-1-phosphate evokes unique segment-specific vasoconstriction of the renal microvasculature. J Am Soc Nephrol 25:1774-85

Showing the most recent 10 out of 25 publications