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

项目摘要 患有II型糖尿病（T2 DM）和代谢综合征（MS）的个体显示过氧化物酶体活性降低 增殖物激活受体γ（PPARγ），并经常发展成盐敏感性高血压（SS HT）。过氧化物酶体增殖体激活受体γ 噻唑烷二酮类（TZDs）激活可降低T2 DM和MS患者的血压。此外， 由显性失活突变（如P467 L）引起的，通过配体阻断PPARγ活化， 在人类中，这些突变的选择性表达在血管平滑肌（VSM）中， 在小鼠（S-P467 L）中重现人HT，表明血管PPARγ受损是因果关系。使用S-P467 L 小鼠作为血管PPARγ损伤模型，我提供了令人信服的初步数据，支持 创新的概念，即在VSM中，PPARγ损伤的有害作用可能是由增强的 PGE 2/E-前列腺素受体3（EP 3）信号在肾小球前阻力血管（小叶间动脉和 传入小动脉），导致肾血管阻力增加，并在过量盐期间使肾血流变钝 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， 在喂食4%高盐饮食的S-P467 L小鼠中增加钠潴留。我们和其他人以前发表过 血管中的过氧化物酶体增殖物激活受体γ通过抗氧化基因的转录调节来防止氧化应激。损失 过氧化物酶体增殖物激活受体γ介导的抗氧化反应可能通过降低肾微血管中NO的生物利用度， NO和活性氧如超氧化物之间的不平衡。K 01奖项的目标是 探讨血管过氧化物酶体增殖物激活受体γ（PPARγ）受损导致盐敏感性的肾脏机制。目标1将测试 假设a）血管PPARγ的损伤通过增强PGE 2/EP 3信号传导而减弱肾血流 B）EP 3的药理学抑制降低肾血管阻力，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） 血管过氧化物酶体增殖物激活受体γ导致NOS介导的NO生成减少和/或抗氧化防御受损， 肾脏，和B）肾内NO缺乏损害尿钠排泄，并有助于在过氧化物酶体增殖物激活受体γ损伤期间的SS-HT。 成功完成指导科学家发展补助金将使我获得必要的技能， 专业知识过渡到独立的学术界的高血压研究，重点是肾血管 生物学、氧化还原生物学和肾小管生理学。

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.