Novel Mechanisms Regulating Renal Perfusion and Kidney Redox Biology: Role in Salt Sensitive Hypertension

调节肾灌注和肾脏氧化还原生物学的新机制：在盐敏感性高血压中的作用

• 批准号: 10582079
• 负责人: Jing Wu
• 金额: $ 15.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-06 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582079
• 关键词: Academia; Animals; Antiinflammatory Effect; Antioxidants; Arteries; Attenuated; Biological Availability; Biology; Blood Pressure; Blood Vessels; Cardiovascular system; Cells; Cerebrovascular Circulation; Chronic Kidney Failure; Clinical Research; Data; Development; Dinoprostone; Dominant-Negative Mutation; Epithelial; Equilibrium; Excess Dietary Salt; Excretory function; Exhibits; Financial compensation; Functional disorder; Furosemide; Generations; Genes; Genetic; Goals; Grant; Human; Hypertension; Impairment; Individual; Interlobular Artery; Kidney; Ligands; Mediating; Mentored Research Scientist Development Award; Mentors; Metabolic syndrome; Modeling; Mus; Mutation; Myocardial Infarction; NOS1 gene; NOS2A gene; Natriuresis; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Oxidative Stress; PPAR gamma; Pathway interactions; Perfusion; Pharmacology; Physiology; Production; Prostaglandin E Receptor; Prostaglandins; Protein Isoforms; Publishing; Reactive Oxygen Species; Receptor Signaling; Renal Blood Flow; Research; Resistance; Risk Factors; Role; Scientist; Signal Transduction; Sodium; Sodium Chloride; Stroke; Superoxides; Testing; Thiazolidinediones; Transcriptional Regulation; Tubular formation; Vascular Endothelium; Vascular Smooth Muscle; Vascular resistance; Vasodilation; Water; antagonist; arteriole; blood glucose regulation; blood pressure reduction; cofactor; early onset; hemodynamics; high salt diet; improved; innovation; kidney dysfunction; kidney vascular structure; macrophage; mortality; novel; prevent; programs; receptor; response; salt intake; salt sensitive hypertension; selective expression; skills; symporter; transcription factor

PROJECT SUMMARY Individuals with type II diabetes (T2DM) and metabolic syndrome (MS) display decreased activity of peroxisome proliferator activated receptor gamma (PPARγ) and often develop salt-sensitive hypertension (SS HT). PPARγ activation by thiazolidinediones (TZDs) lowers blood pressure in T2DM and MS. Moreover, PPARγ impairment caused by dominant negative mutations (e.g. P467L) that block PPARγ activation by ligands cause severe early onset HT in humans, while selective expression of these mutations in vascular smooth muscle (VSM) recapitulates human HT in mice (S-P467L), suggesting impairment of vascular PPARγ is causal. Using S-P467L mice as a model of vascular PPARγ impairment, I have provided compelling preliminary data supporting an innovative concept that the detrimental effects of PPARγ impairment in VSM may be mediated by enhanced PGE2/E-Prostanoid Receptor 3 (EP3) signaling in pre-glomerular resistance vessels (interlobular artery and afferent arterioles), causing increased renal vascular resistance and blunted renal blood flow during excess salt loading. The blunted renal perfusion is associated with decreased intrarenal nitric oxide (NO) bioavailability and increased sodium retention in S-P467L mice fed a 4% high salt diet. We and others have previously published that vascular PPARγ prevents oxidative stress through transcriptional regulation of antioxidant genes. Loss of PPARγ-mediated antioxidant responses may decrease NO bioavailability in renal microvessels through an imbalance between NO and reactive oxygen species such as superoxide. The goal of this K01 award is to investigate the renal mechanisms of salt sensitivity caused by the impairment of vascular PPARγ. Aim 1 will test the hypotheses that a) impairment of vascular PPARγ blunts renal blood flow by enhancing PGE2/EP3 signaling in renal microvessels, and b) pharmacological inhibition of EP3 decreases renal vascular resistance, improves renal perfusion, and attenuates SS HT during PPARγ impairment. Aim 2 will test the hypotheses that a) impaired vascular PPARγ results in decreased NOS-mediated NO generation and/or impaired antioxidant defense in the kidney, and b) intrarenal NO deficiency impairs natriuresis and contributes to SS HT during PPARγ impairment. Successful completion of the mentored scientist development grant will allow me to acquire necessary skills and expertise to transition to independence in the academia of hypertension research focusing on renal vascular biology, redox biology, and tubular physiology.

项目概要 患有 II 型糖尿病 (T2DM) 和代谢综合征 (MS) 的个体过氧化物酶体活性降低 增殖物激活受体γ (PPARγ) 并经常发展为盐敏感性高血压(SS HT)。 PPARγ 噻唑烷二酮 (TZD) 的激活可降低 T2DM 和 MS 患者的血压。此外，PPARγ损伤 由显性失活突变（例如 P467L）引起，配体阻断 PPARγ 激活，导致严重的早期 人类发生 HT，而这些突变在血管平滑肌 (VSM) 中选择性表达 重现了小鼠体内的人类 HT (S-P467L)，表明血管 PPARγ 的损伤是因​​果关系。使用S-P467L 小鼠作为血管 PPARγ 损伤的模型，我提供了令人信服的初步数据支持 创新概念认为，VSM 中 PPARγ 损伤的有害影响可能是通过增强的 肾小球前阻力血管（小叶间动脉和小叶间动脉）中的 PGE2/E-前列腺素受体 3 (EP3) 信号传导 传入小动脉），过量盐导致肾血管阻力增加和肾血流减弱 加载中。肾灌注减弱与肾内一氧化氮 (NO) 生物利用度降低有关 饲喂 4% 高盐饮食的 S-P467L 小鼠钠潴留增加。我们和其他人之前已经发表过 血管 PPARγ 通过抗氧化基因的转录调节来预防氧化应激。损失 PPARγ介导的抗氧化反应可能通过以下方式降低肾微血管中NO的生物利用度： NO 和活性氧（例如超氧化物）之间的不平衡。 K01 奖的目标是 研究血管PPARγ损伤引起盐敏感性的肾脏机制。目标 1 将进行测试 假设 a) 血管 PPARγ 损伤通过增强 PGE2/EP3 信号传导来减弱肾血流 b) EP3 的药理学抑制可降低肾血管阻力，改善 肾灌注，并在 PPARγ 损伤期间减弱 SS HT。目标 2 将检验以下假设：a) 受损 血管 PPARγ 导致 NOS 介导的 NO 生成减少和/或抗氧化防御受损 b) 肾内 NO 缺乏会损害尿钠排泄，并在 PPARγ 损伤期间导致 SS HT。 成功完成指导科学家发展补助金将使我能够获得必要的技能和 专注于肾血管的高血压学术界向独立过渡的专业知识 生物学、氧化还原生物学和肾小管生理学。