Regulation of Renal Function and BP by Thromboxane

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 DESCRIPTION (provided by applicant): Hypertensive chronic kidney disease (CKD) is a major cause of cardiovascular disease (CVD) and death but neither a lower BP goal nor the use of any specific drug has halted its relentless progression. The promise of nuclear factor-erythroid-2-related factor 2 (Nrf-2) activators (such as bardoxolone methyl) for prevention of CKD progression was dashed when they were reported to have serious adverse CVD effects. We demonstrated that Nrf-2 in endothelial cells transcribed genes for anti-oxidants and protective pathways. However Nrf-2 in vascular smooth muscle and proximal tubule cells also transcribed genes that activated signaling via the thromboxane prostanoid (TP) receptor. These genes included cyclooxygenase (COX) 2, thromboxane synthase and TP-receptor. Moreover, tBHQ given during angiotensin to activate Nrf-2, increased blood pressure, renal vascular resistance and proximal tubule fluid reabsorption in mice. The first aim will use Nrf-2 and TP receptor +/+ and -/- mice to test the hypothesis that that Nrf-2 upregulates signaling via COX2, and TP-Rs to cause hypertension, enhanced proximal tubule (PT) reabsorption, tubuloglomerular feedback (TGF) and angiotensin-induced constriction of renal afferent arterioles that predispose to fluid retention, hypertension, and heart failure which were the adverse effects encountered in patients treated with bardoxolone. Hypertension with a failed myogenic response leads to barotrauma in damaged kidneys. Blockade of TP-Rs in mice with CKD enhanced (restored) myogenic contractions. The second aim will use global and smooth muscle specific TP receptor +/+ and -/- mice in a DOCA/salt model of low renin, hypertension, in which we find activation of the COX2/thromboxane/TP receptor pathways. We will test the hypothesis that salt-sensitive hypertensive renal damage depends on TP receptors. Will study how TP receptors regulate BP, components of renal autoregulation and renal hypoxia in this model since these are fundamental pathways leading to renal damage. These studies will explore new roles for TP receptors in adverse renal and cardiovascular events following renal damage and thereby may lead to new indications for TP receptor antagonists in renal protection.