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.