Regulation of Renal Function and BP by Thromboxane

 描述(申请人提供)：高血压慢性肾脏病(CKD)是心血管疾病(CVD)和死亡的主要原因，但较低的血压目标和任何特定药物的使用都没有阻止其持续发展。核因子-红系相关因子-2(NRF-2)激动剂(如甲基巴多松)预防CKD进展的希望破灭了，因为有报道称它们有严重的不利CVD影响。我们证明了内皮细胞中的NRF-2转录了抗氧化和保护途径的基因。然而，血管平滑肌和近端小管细胞中的NRF-2也转录了通过血栓素前列腺素(TP)受体激活信号的基因。这些基因包括环氧合酶(COX)2、血栓素合成酶和TP受体。此外，在血管紧张素期间给予TBHQ以激活NRF-2，增加小鼠的血压、肾血管阻力和近端小管液的重吸收。第一个目标将使用NRF-2和TP受体+/+和-/-小鼠来测试假设，即NRF-2通过COX2上调信号，TP-Rs导致高血压、近端小管(PT)重吸收增强、肾小管球反馈(TGF)和血管紧张素诱导的肾传入小动脉收缩，这些都是接受巴多龙治疗的患者遇到的不良反应，容易发生液体滞留、高血压和心力衰竭。高血压伴失败的肌源性反应会导致受损肾脏的气压伤。阻断慢性肾脏病增强(恢复)肌源性收缩小鼠的TP-Rs。第二个目标将在DOCA/SALT低肾素高血压模型中使用全局和平滑肌特异性TP受体+/+和-/-小鼠，在该模型中，我们发现COX2/血栓烷/TP受体通路被激活。我们将验证盐敏感型高血压肾损害依赖于TP受体的假设。在这个模型中，我将研究TP受体如何调节血压、肾脏自我调节的成分和肾脏缺氧，因为这些都是导致肾脏损伤的基本途径。这些研究将探索TP受体在肾损伤后不良肾脏和心血管事件中的新作用，从而可能导致TP受体拮抗剂在肾脏保护中的新适应症。

 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.