Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation

对患者的流行病学和预后研究以及对啮齿动物模型的研究表明，肾脏缺血 肾损伤和单侧梗阻性尿路病带来长期后果：高血压和慢性 肾脏疾病。主要的病理生理因素包括肾血流动力学受损、内皮扩张器 功能障碍和内皮细胞炎症。因为肾脏微循环缺乏有效的再生 容量，对微循环的急性损害可导致肾脏血流动力学的长期变化， 使患者易患高血压和慢性肾脏疾病。 花生四烯酸代谢产物环氧二十碳三烯酸(EETs)可增加肾血流量，改善肾功能。 内皮细胞功能。目前尚不清楚CYP2C环氧合酶、可溶性环氧化物水解酶的作用 (SEH)和区域异构体EETs对盐敏感型高血压和梗阻性慢性肾脏疾病的影响 尿病和肾脏缺血性损伤。我们假设内皮细胞EET水平降低会导致内皮细胞 肾缺血损伤或尿路梗阻后的肾功能障碍和肾血流动力学受损。 该项目的近期目标是确定内皮EET改善内皮的能力。 依赖传入小动脉扩张，以减少内皮炎症，并防止盐敏感 单侧输尿管梗阻或缺血/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 CYP2C、sEH和EETs的调控。 我们将通过完成三个目标来实现我们的眼前目标。 目标1将检验以下假设：EET水平或EET功能降低有助于盐分的发展。 UUO或I/R肾损伤后的敏感性高血压和慢性肾脏疾病。 Aim 2将验证增加内皮EET水平将改善肾微血管内皮细胞的假设 UUO或I/R肾损伤后的功能，以预防盐敏感型高血压和慢性肾脏疾病。 目标3将验证这一假设，即提高EET水平的药物方法可以防止长期 UUO或I/R肾损伤后盐敏感型高血压和慢性肾损害。 因此，我们的发现有望推动这一领域向前发展，不仅增强了我们对 UUO或I/R肾损伤导致慢性肾脏疾病的病理生理机制 导致了新的治疗方法。

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.