Renal Endothelial Dysfunction in Salt-Sensitive Hypertension

盐敏感性高血压中的肾内皮功能障碍

基本信息

批准号：
7433776
负责人：
John D Imig
金额：
$ 29.09万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433776
关键词：
11,12-epoxy-5,8,14-eicosatrienoic acid Accounting Acids Angiotensin II Animal Model Anti-Inflammatory Agents Anti-inflammatory Antihypertensive Agents Blood Pressure Cardiovascular Diseases Conscious Cytokine Suppression Development Diet Disruption End stage renal failure Endothelium Enzymes Epoxide hydrolase Failure Functional disorder Genes Hemorrhage Histology Human Hydrolase Hypertension Incidence Injury Kidney Kidney Diseases Kidney Failure Link Measures Microcirculation Organ Pathway interactions Patients Physiological Production Property Prothrombin Rattus Regulation Research Personnel Resistance Rho-associated kinase Sodium Chloride Staging Testing Vascular resistance Video Microscopy base blood pressure regulation cytokine glomerular function improved inhibitor/antagonist kidney vascular structure novel pressure programs protein expression receptor research study response salt sensitive urinary

项目摘要

End stage renal disease (ESRD) is manifest in hypertension and the progression of renal failure is accelerated by a high salt diet. In human patients and angiotensin II salt-sensitive hypertensive animal models, endothelial dysfunction and increased renal vascular resistance are observed as hypertension progresses and ESRD becomes evident. Another common feature of salt-sensitive hypertension is the inability of the kidney to properly increase epoxyeicosatrienoic acid (EET) levels. Others and we have provided compelling evidence that CYP450-derived EETs have anti-hypertensive properties and are endothelial-derived hyperpolarizing factors (EDHF) in the kidney. EETs also possess anti-inflammatory actions that could protect the kidney vasculature from injury during hypertension. Cytokine suppression of kidney EET production is a mechanism that could explain endothelial dysfunction and glomerular injury associated with salt-sensitive hypertension. Based on these observations, we hypothesis that a failure to properly increase kidney EET levels in response to high dietary salt contributes to endothelial dysfunction, glomerular injury, and salt-sensitivity in angiotensin II hypertension. We will determine the effects of salt diet, cytokines and arterial blood pressure on EDHF regulation, afferent arteriolar endothelial function and glomerular injury in salt-sensitive hypertension. The proposed studies will employ newly developed highly selective epoxide hydrolase inhibitors that increase EET levels to determine their ability to lower arterial blood pressure and improve renal microvascular function in angiotensin II salt-sensitive hypertension. Collectively, the proposed experiments in this application will provide novel information on the interaction between cytokines and EET levels in the long-term regulation of blood pressure and renal microvascular and glomerular function during angiotensin II salt-sensitive hypertension.

终末期肾病（ESRD）表现为高血压，高盐饮食会加速肾衰竭的进展。在人类患者和血管紧张素 II 盐敏感性高血压动物模型中，随着高血压进展和 ESRD 变得明显，观察到内皮功能障碍和肾血管阻力增加。盐敏感性高血压的另一个常见特征是肾脏无法适当增加环氧二十碳三烯酸（EET）水平。其他人和我们提供了令人信服的证据，证明 CYP450 衍生的 EET 具有抗高血压特性，并且是肾脏中内皮衍生的超极化因子 (EDHF)。 EET 还具有抗炎作用，可以保护肾血管系统免受高血压期间的损伤。细胞因子抑制肾脏 EET 产生是一种可以解释与盐敏感性高血压相关的内皮功能障碍和肾小球损伤的机制。基于这些观察，我们假设，未能适当增加肾脏 EET 水平来应对高盐饮食会导致血管紧张素 II 高血压中的内皮功能障碍、肾小球损伤和盐敏感性。我们将确定盐饮食、细胞因子和动脉血压对盐敏感性高血压的 EDHF 调节、传入小动脉内皮功能和肾小球损伤的影响。拟议的研究将采用新开发的高选择性环氧化物水解酶抑制剂，该抑制剂可提高 EET 水平，以确定其降低血管紧张素 II 盐敏感性高血压的动脉血压和改善肾微血管功能的能力。总的来说，拟议的该应用中的实验将提供关于细胞因子和 EET 水平之间的相互作用在血管紧张素 II 盐敏感性高血压期间长期调节血压以及肾微血管和肾小球功能的新信息。