Regulation of Renal Function and BP by Thromboxane

血栓素对肾功能和血压的调节

• 批准号: 9265467
• 负责人: CHRISTOPHER S WILCOX
• 金额: $ 34.99万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-21 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265467
• 关键词: Acetates; Adverse effects; Angiotensin II; Angiotensins; Antioxidants; Back; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chronic Kidney Failure; Clinical Trials; Congestive Heart Failure; Conscious; DOCA; Deoxycorticosterone; Diabetic Nephropathy; Disease Progression; Dysbarism; Endothelial Cells; Enzymes; Event; Excretory function; Feedback; Fibrosis; Genes; Goals; Heart; Heart failure; Homeostasis; Hypertension; Hypoxia; Impairment; Inflammation; Kidney; Kidney Diseases; Lead; Liquid substance; Mediating; Mediator of activation protein; Modeling; Mus; Myocardial; Myocarditis; Nephrons; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Prevention; Prostaglandins; Proteins; Proteinuria; Regulation; Renal Blood Flow; Renal function; Renin; Reporting; Research; Role; Signal Transduction; Smooth Muscle; Sodium; Sodium Chloride; Testing; Therapeutic; Thromboxane A2; Thromboxanes; Tubular formation; Vascular Smooth Muscle; Vascular resistance; Work; arteriole; blood pressure reduction; blood pressure regulation; constriction; cyclooxygenase 2; glomerulosclerosis; hemodynamics; improved; kidney vascular structure; loss of function; low renin hypertension; mitochondrial dysfunction; novel; nuclear factor-erythroid 2; pressure; prevent; protein expression; public health relevance; receptor; renal hypoxia; response; salt sensitive; salt sensitive hypertension; vasoconstriction

 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.

 描述（由申请人提供）：高血压慢性肾病（CKD）是心血管疾病（CVD）和死亡的主要原因，但无论是降低血压目标还是使用任何特定药物都无法阻止其无情的进展。核因子-红细胞-2-相关因子2（Nrf-2）激活剂（如甲基巴多索龙）用于预防CKD进展的前景破灭时，他们被报道有严重的不良CVD影响。我们证明了内皮细胞中的Nrf-2转录抗氧化剂和保护途径的基因。然而，血管平滑肌和近端小管细胞中的Nrf-2也转录通过血栓烷前列腺素（TP）受体激活信号传导的基因。这些基因包括环氧合酶（考克斯）2、血栓素合酶和TP受体。此外，在血管紧张素活化Nrf-2期间给予tBHQ，增加小鼠血压、肾血管阻力和近端小管液体重吸收。第一个目的将使用Nrf-2和TP受体+/+和-/-小鼠来测试以下假设：Nrf-2通过COX 2和TP-Rs上调信号传导，从而引起高血压、增强的近端小管（PT）重吸收、肾小管肾小球反馈（TGF）和血管紧张素诱导的肾传入小动脉收缩，其易患液体潴留、高血压、和心力衰竭，这是在用巴多索龙治疗的患者中遇到的副作用。高血压伴肌源性反应失败可导致受损肾脏气压伤。在患有CKD的小鼠中阻断TP-Rs增强（恢复）肌源性收缩。第二个目标将在低肾素、高血压的DOCA/盐模型中使用整体和平滑肌特异性TP受体+/+和-/-小鼠，其中我们发现COX 2/血栓烷/TP受体途径的激活。我们将检验盐敏感性高血压肾损害依赖于TP受体的假设。将研究TP受体如何调节血压，肾脏自动调节的组成部分和肾脏缺氧在这个模型中，因为这些是导致肾脏损害的基本途径。这些研究将探索TP受体在肾损伤后不良肾和心血管事件中的新作用，从而可能导致TP受体拮抗剂在肾保护中的新适应症。