Renal Endothelial Dysfunction in Salt-Sensitive Hypertension

盐敏感性高血压中的肾内皮功能障碍

• 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
• 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

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，高盐饮食加速了肾衰竭的进展。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共同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表明，CYP450衍生的雌二醇具有抗高血压特性，是肾脏中的内皮衍生超极化因子（EDHF）。雌二醇还具有抗炎作用，可保护肾血管免受高血压损伤。细胞因子抑制肾脏EET的产生是一种机制，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。基于这些观察，我们假设，未能适当增加肾脏EET水平，以应对高饮食盐有助于血管紧张素II高血压的内皮功能障碍，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中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，增加EET水平，以确定其降低动脉血压和改善血管紧张素II盐敏感性高血压患者肾微血管功能的能力。总体而言，拟议的 本申请中的实验将提供关于在血管紧张素II盐敏感性高血压期间长期调节血压和肾微血管和肾小球功能中细胞因子和EET水平之间相互作用的新信息。