Hypertension (HT) affects ~48% of the US population. Increased renal sodium (Na+) retention is a major contributor to the development of HT. The renal angiotensin type-1 receptor (AT1R), activated predominantly by angiotensin (Ang) II, is both necessary and sufficient for inducing and sustaining HT during Ang II infusion. Increased Na+ reabsorption in renal proximal tubule cells (RPTC) is a major determinant of this response. The role of the angiotensin type-2 receptor (AT2R) in Na+ excretion and blood pressure (BP) control is less well understood. AT2Rs are expressed in adult kidneys primarily in RPTC. Our past studies provided evidence for a major role of RPT AT2Rs in the inhibition of renal Na+ reabsorption. Recently, we identified a defect in AT2R- mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates HT and can be circumvented by direct renal administration of cyclic GMP (cGMP). Our results suggest that defective AT2R-induced natriuresis may contribute to the pathogenesis of HT in SHR. The goals of this project are to (1) conclusively demonstrate the role of AT2Rs in BP control using our newly developed RPTC-AT2R deficient mice, (2) identify downstream AT2R signaling pathways mediating natriuresis, (3) characterize the primary RPTC AT2R defect(s) in SHR at the cellular and molecular levels, and (4) validate renal cGMP and protein phosphatase 2A (PP2A) activation as specific therapeutic targets for HT. These goals will be addressed under three specific aims: (1) To test the hypothesis that RPT AT2Rs are required for the regulation of Na+ excretion and blood pressure; (2) To test the hypothesis that protein phosphatase 2A (PP2A) initiates and sustains RPTC AT2R signaling to induce natriuresis; and (3) To test the hypothesis that intrarenal PP2A activation and/or restoration of cGMP levels/signaling can normalize blood pressure in hypertensive SHR and RPTC-selective AT2R knockout mice. The project will apply a combination of state-of-the-art in vivo and cellular and molecular techniques to determine mechanisms by which AT2R regulates Na+ excretion and BP. These studies will help define the pathophysiology of HT and open the door to new classes of drugs for the treatment of human primary HT.
Hypertension (high blood pressure), present in almost 50% of the population of the United States, is a major risk factor for heart and blood vessel disease leading to premature death and disability. Retention of salt and water by the kidney is required for hypertension to develop. This application will increase our understanding of the mechanisms whereby the kidney renin-angiotensin system regulates salt and water excretion, suggesting new molecular targets for the treatment and prevention of hypertension.
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