Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation

对患者的流行病学和结局研究以及啮齿动物模型的研究表明，肾缺血 肾损伤和单侧梗阻性尿路病带来长期后果：高血压和慢性 肾病主要的病理生理因素包括肾血流动力学受损、内皮扩张剂 功能障碍和内皮细胞炎症。由于肾脏微循环缺乏有效的再生 容量，对微循环的急性损伤可导致肾血流动力学的长期变化， 使患者易患高血压和慢性肾病。 一类花生四烯酸代谢物，环氧二十碳三烯酸（ESTA）增加肾血流量，并改善 内皮细胞功能尚不清楚CYP 2C环氧酶、可溶性环氧化物水解酶 (sEH)和区域异构体雌二醇对盐敏感性高血压和阻塞性肾病后的慢性肾脏疾病的作用 泌尿系疾病和肾缺血性损伤。我们假设内皮细胞EET水平降低导致内皮细胞 肾缺血性损伤或尿路梗阻后肾功能障碍和肾血流动力学受损。 该项目的直接目标是确定内皮细胞激活素改善内皮细胞的能力， 依赖性传入小动脉扩张，以减少内皮炎症，并防止盐敏感性 单侧输尿管梗阻（UUO）或缺血/再灌注后高血压和慢性肾脏疾病 （I/R）肾损伤。该项目将利用药理学以及全球和组织特异性遗传 操纵CYP 2C、sEH和EH。 我们将通过完成三个目标来实现我们的近期目标。 目的1将检验EET水平或EET功能降低有助于盐代谢的发展这一假设。 敏感性高血压和UUO或I/R肾损伤后的慢性肾病。 目的2将检验增加内皮EET水平将改善肾微血管内皮细胞的假设。 在UUO或I/R肾损伤后发挥作用，预防盐敏感性高血压和慢性肾病。 目的3将检验增加EET水平的药理学方法可以预防长期的EET水平降低的假设。 盐敏感性高血压和UUO或I/R肾损伤后的慢性肾损伤。 因此，我们的研究结果不仅提高了我们对环境的理解， UUO或I/R肾损伤导致慢性肾病的病理生理机制， 从而产生新的治疗方法。

Epidemiological and outcomes studies in patients, as well as studies in rodent models, reveal that renal ischemic kidney injury and unilateral obstructive uropathy brings on long-term consequences: hypertension and chronic kidney disease. Major pathophysiological contributors include impaired renal hemodynamics, endothelial dilator dysfunction, and endothelial cell inflammation. Because the renal microcirculation lacks efficient regenerative capacity, acute damage to the microcirculation can lead to long-term changes in renal hemodynamics that predispose patients to hypertension and chronic kidney disease. A class of arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs) increase renal blood flow and improve endothelial cell function. Not known is the contribution of CYP2C epoxygenases, soluble epoxide hydrolase (sEH), and regioisomeric EETs to salt-sensitive hypertension and chronic kidney disease following obstructive uropathy and renal ischemic injury. We hypothesize that decreased endothelial EET levels result in endothelial dysfunction and impaired renal hemodynamics following renal ischemic injury or urinary tract obstruction. The immediate goals of this project are to determine the ability for endothelial EETs to improve endothelial- dependent afferent arteriolar dilation, to decrease endothelial inflammation, and to prevent salt-sensitive hypertension and chronic kidney disease following unilateral ureter obstruction (UUO) or ischemia/reperfusion (I/R) kidney injury. This project will utilize pharmacological as well as global and tissue-specific genetic manipulation of CYP2C, sEH, and EETs. We will obtain our immediate goals by completing three aims. Aim 1 will test the hypothesis that decreased EET levels or EET function contributes to the development of salt- sensitive hypertension and chronic kidney disease following UUO or I/R kidney injury. Aim 2 will test the hypothesis that increasing endothelial EET levels will improve renal microvascular endothelial function following UUO or I/R kidney injury to prevent salt-sensitive hypertension and chronic kidney disease. Aim 3 will test the hypothesis that pharmacological approaches to increase EET levels can prevent the long-term salt-sensitive hypertensive and chronic kidney injury following UUO or I/R kidney injury. Accordingly, our findings promise to advance the field forward by not only enhancing our understanding of the pathophysiological mechanisms whereby UUO or I/R kidney injury leads to chronic kidney disease but also leading to new therapeutic treatments.