Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation

内皮环氧合酶、肾脏损伤和血压调节

• 批准号: 10625377
• 负责人: John D Imig
• 金额: $ 51.47万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625377
• 关键词: Acids; Acute; Acute Renal Failure with Renal Papillary Necrosis; Arachidonic Acids; Attenuated; Bilateral; Blood Vessels; Blood flow; CYP2C19 gene; Cell Adhesion Molecules; Cell Culture Techniques; Cell physiology; Chronic; Chronic Kidney Failure; Cytochrome P450; Data; Development; Dilator; Endothelial Cells; Endothelium; Epoxide hydrolase; Functional disorder; Glomerular Filtration Rate; Goals; Hydrolysis; Hypertension; Impairment; Inflammation; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Calculi; Kidney Diseases; Microcirculation; Modeling; Outcome; Outcome Study; Patients; Recovery; Regenerative capacity; Renal Blood Flow; Reperfusion Injury; Reperfusion Therapy; Rodent Model; Testing; Therapeutic; Tissues; Tubular formation; Ureteral obstruction; Vascular Endothelial Cell; Vascular Endothelium; Vasodilation; analog; blood pressure reduction; blood pressure regulation; density; design; endothelial dysfunction; epidemiology study; genetic manipulation; glomerular filtration; hemodynamics; hypertensive; improved; inhibitor; ischemic injury; novel; novel therapeutics; pharmacologic; prevent; protective effect; renal artery; renal ischemia; repaired; response; restoration; salt sensitive; salt sensitive hypertension; urinary tract obstruction

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.

患者的流行病学和结果研究以及啮齿动物模型中的研究表明肾脏缺血性 肾脏损伤和单侧阻塞性泌尿病会带来长期后果：高血压和慢性 肾脏疾病。主要的病理生理贡献者包括肾脏血流动力学受损，内皮扩张剂 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会导致肾脏血流动力学的长期变化 易患高血压和慢性肾脏疾病。 一类花生四烯酸代谢产物，环氧卫生酸（EET）增加肾血流并改善 内皮细胞功能。尚不清楚的是CYP2C环氧酶，可溶性环氧水解酶的贡献 （SEH）和盐敏感性高血压和慢性肾脏疾病的区域性异构体EET后阻塞性疾病 尿道病和肾脏缺血性损伤。我们假设内皮EET水平降低导致内皮 肾脏缺血性损伤或尿路阻塞后功能障碍和肾脏血流动力学受损。 该项目的直接目标是确定内皮EET改善内皮的能力 依赖性传入小动脉扩张，以减少内皮炎症并防止盐敏感 单侧输尿管阻塞（UUO）或缺血/再灌注后的高血压和慢性肾脏疾病 （I/R）肾脏受伤。该项目将利用药理以及全球和组织特异性遗传 CYP2C，SEH和EET的操作。 我们将通过完成三个目标来实现我们的直接目标。 AIM 1将检验以下假设：EET水平或EET功能降低有助于盐的发展 UUO或I/R肾脏损伤后，敏感的高血压和慢性肾脏疾病。 AIM 2将检验以下假设，即增加内皮EET水平将改善肾脏微血管内皮 UUO或I/R肾脏损伤后的功能，以防止盐敏感性高血压和慢性肾脏疾病。 AIM 3将检验以下假设：提高EET水平的药理学方法可以防止长期 UUO或I/R肾脏损伤后，对盐敏感的高血压和慢性肾脏损伤。 因此，我们的发现有望通过增强我们对 UUO或I/R肾脏损伤导致慢性肾脏疾病的病理生理机制，但也 导致新的治疗疗法。

项目成果

Epoxylipids and soluble epoxide hydrolase in heart diseases.

• DOI: 10.1016/j.bcp.2021.114866
• 发表时间: 2022-01
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Imig JD;Cervenka L;Neckar J
• 通讯作者: Neckar J

Epoxyeicosatrienoic Acid Analog and 20-HETE Antagonist Combination Prevent Hypertension Development in Spontaneously Hypertensive Rats.

• DOI: 10.3389/fphar.2021.798642
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Baranowska I;Gawrys O;Walkowska A;Olszynski KH;Červenka L;Falck JR;Adebesin AM;Imig JD;Kompanowska-Jezierska E
• 通讯作者: Kompanowska-Jezierska E

Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats.

添加内皮素 A 受体阻断会破坏肾素-血管紧张素和可溶性环氧化物水解酶联合抑制的有益效果：5/6 肾切除 Ren-2 转基因高血压大鼠慢性肾病病程的研究。

• DOI: 10.1159/000504137
• 发表时间: 2019
• 期刊: Kidney & blood pressure research
• 影响因子: 2.8
• 作者: ČertíkováChábová,Věra;Kujal,Petr;Vaňourková,Zdeňka;Škaroupková,Petra;Sadowski,Janusz;Kompanowska-Jezierska,Elzbieta;Tesař,Vladimír;Hammock,Bruce;Imig,John;Maxová,Hana;Červenka,Luděk;Vaněčková,Ivana
• 通讯作者: Vaněčková,Ivana

Bioactive lipids in hypertension.

高血压中的生物活性脂质。

• DOI: 10.1016/bs.apha.2023.01.001
• 发表时间: 2023
• 期刊: Advances in pharmacology (San Diego, Calif.)
• 作者: Imig,JohnD

Dual soluble epoxide hydrolase inhibitor - farnesoid X receptor agonist interventional treatment attenuates renal inflammation and fibrosis.

• DOI: 10.3389/fimmu.2023.1269261
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Khan, Md. Abdul Hye;Nolan, Benjamin;Stavniichuk, Anna;Merk, Daniel;Imig, John D.
• 通讯作者: Imig, John D.