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

项目总结 2型糖尿病(T2 DM)和代谢综合征(MS)患者的过氧化物酶活性降低 增殖物激活受体γ(PPARγ)，常发展成盐敏感型高血压(SS-HT)。PPARγ 噻唑烷二酮类药物(TZDS)可降低T2 DM和MS患者的血压。此外，PPARγ损伤 由配体阻断PPARγ激活的显性负突变(例如P467L)引起的严重早期 在人类中起病，而这些突变在血管平滑肌(VSM)中选择性表达 在小鼠中概括了人的HT(S-P467L)，表明血管PPARγ的损伤是原因所致。使用S-P467L 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 VSM中PPARγ损伤的有害影响可能通过增强的 PGE2/E-前列腺素受体3(EP3)在肾小球前阻力血管(小叶间动脉和 传入小动脉)，导致高盐时肾血管阻力增加和肾血流量变钝 正在装车。钝性肾脏灌注与肾内一氧化氮(NO)生物利用度降低有关， 饲喂4%高盐饲料的S-P467L小鼠的钠存留率增加。我们和其他人之前已经发表了 血管PPARγ通过对抗氧化基因的转录调控来防止氧化应激。损失 PPARγ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和超氧化物等活性氧物种之间的失衡。这一K01奖项的目标是 探讨血管PPARγ损伤引起的肾脏盐敏感性机制。AIM 1将测试 A)血管PPARγ损伤通过增强PGE_2/EP3信号使肾血流量变钝的假说 和b)药物抑制EP3降低肾血管阻力，改善 在PPARγ损伤时，肾脏灌流，并减轻SS-HT。目标2将检验以下假设：a)损害 血管PPARγ导致一氧化氮合酶介导的NO生成减少和/或抗氧化防御受损 B)肾内NO缺乏会损害钠尿，并在PPARγ受损时导致SS-HT。 成功完成科学家导师发展基金将使我获得必要的技能和 专注于肾血管的高血压研究学术界向独立性过渡的专业知识 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.