Regulation of Renal Function and BP by Thromboxane

血栓素对肾功能和血压的调节

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：高血压慢性肾脏疾病（CKD）是心血管疾病（CVD）和死亡的主要原因，但BP的目标均不是较低的BP目标，也不使用任何特定药物都停止了其不断的进展。核因子 - 金属-2相关因子2（NRF-2）活化剂（例如bardoxolone甲基）预防CKD进展的承诺在据报道具有严重的逆向CVD效应时破灭了。我们证明内皮细胞中的NRF-2转录了抗氧化剂和受保护途径的基因。但是，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前类动物（TP）受体激活信号的基因。这些基因包括环氧合酶（COX）2，血栓烷合酶和TP受体。此外，在血管紧张素期间给出的TBHQ激活NRF-2，血压升高，肾血管耐药性和小鼠近端管流体的吸收。 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 tube (PT) reabsorption, tubeloglomerular feedback (TGF) and angiotensin-induced constriction of renal afferent arterioles that predispose to fluid保留，高血压和心力衰竭，这是用barodoxolone治疗的患者遇到的不良反应。肌源性反应失败的高血压导致损伤肾脏中的Barotrauma。 CKD的小鼠中TP-R的阻断增强了（恢复）肌源性收缩。第二个目标将使用低肾素（低肾素，高血压的DOCA/盐模型）中使用全局和平滑肌特异性TP受体 +/ +和 - / - 小鼠，其中我们发现COX2/Thromboxane/TP受体途径的激活。我们将检验以下假设：盐敏感性高血压肾损害取决于TP受体。将研究TP受体在该模型中如何调节BP，肾脏自动调节和肾脏缺氧的成分，因为这些是导致肾脏损害的基本途径。这些研究将在肾脏损伤后提前探索TP受体的新作用，从而导致TP受体拮抗剂在肾脏保护中的新指示。