The Role of PPAR-alpha during Angiotensin II Hypertension

描述(由申请人提供)： 在美国，每四个成年人中就有一个患有高血压，患终末期肾脏疾病的风险增加。尽管在为高血压提供更有效的治疗方面取得了长足的进步，但慢性血压升高仍会导致进行性肾脏损害。最近的研究表明，促炎症细胞因子白介素6(IL-6)在肾损伤和慢性高血压中起重要作用。过氧化物酶体增殖物激活受体(PPAR)-α是一种核激素激活的受体和转录因子，可抑制IL-6的产生和氧化应激，并参与血压调节。在肾脏中，PPAR-α在肾单位近端小管段表达最为丰富。然而，PPAR-α调节肾依赖性慢性高血压的机制尚不清楚。我们在我们的PPAR-α基因敲除(KO)的慢性血管紧张素II(Ang11)诱导的高血压小鼠模型中公布了新的数据，与野生型(WT)对照组相比，该模型显示升压反应和血浆IL-6增加。我们的新发现表明，PPAR-α配体非诺贝特可以降低WT小鼠对Ang11和血浆IL-6的血压反应。在Ang11+非诺贝特治疗期间，与PPAR-αKO小鼠相比，WT小鼠的尿钠排泄增加。因此，这项建议的总体目标是确定PPAR-α通过IL-6依赖途径降低慢性高血压的肾脏机制。我们将进行慢性血压测量，并利用单肾单位微穿刺术来验证中心假设，即PPAR-α的激活通过减少循环中的IL-6和近端小管对Na+的重新吸收来降低慢性Ang11诱导的高血压。在这项提议中，制定了三个特定的目标：1)验证PPAR-α激活通过IL-6依赖机制降低Ang11诱导的高血压的假设；2)确定在Ang11治疗期间PPAR-αKO小鼠血压升高的机制；3)测试PPAR-α激活过程中近端小管对Na+的重吸收减弱的假设。我们的结果提示，了解PPAR-α激活的机制是治疗高血压的一个重要因素，并可能为终末期肾脏疾病的治疗提供有用的治疗药物。(摘要结束)

DESCRIPTION (provided by applicant): One out of every four adults in the United States has hypertension and is at increased risk for the development of end-stage renal disease. Although great strides have been made in providing more effective treatments for hypertension, chronic elevation in blood pressure still results in progressive renal damage. Recent reports indicate that the pro-inflammatory cytokine, interleukin-6 (IL-6), plays an important role in renal injury and chronic hypertension. Peroxisome proliferator-activated receptor (PPAR)-alpha is a nuclear hormone-activated receptor and transcription factor that inhibits, IL-6 production, oxidative stress and has been implicated in blood pressure regulation. In the kidney, PPAR-alpha is expressed most abundantly in the proximal tubule segment of the nephron. However, the mechanism by which PPAR-alpha regulates renal-dependent chronic hypertension is not well-understood. We present new data in our PPAR-alpha knockout (KO) mouse model of chronic Angiotensin II (Angll)-induced hypertension that shows an increased pressor response and plasma IL-6 when compared to wild-type (WT) controls. Our new findings indicate that the PPAR-alpha ligand, fenofibrate, lowers the blood pressure response to Angll and plasma IL-6 in WT mice. During Angll + fenofibrate treatment, urinary Na+ excretion is elevated in WT mice when compared to PPAR-alpha KO mice. Therefore, the overall goal of this proposal is to determine the renal mechanisms by which PPAR-alpha reduces chronic hypertension through an IL-6 dependent pathway. We will conduct chronic blood pressure measurements and utilize the single nephron micro puncture technique to test the central hypothesis that PPAR-alpha activation decreases chronic Angll-induced hypertension by decreasing circulating IL-6 and Na+ re-absorption in the proximal tubule. In this proposal, three specific aims are formulated to: 1) test the hypothesis that PPAR-alpha activation decreases Angll-induced hypertension through an IL-6 dependent mechanism, 2) determine the mechanisms responsible for the increased blood pressure in PPAR-alpha KO mice during Angll treatment 3) test the hypothesis that the proximal tubule re-absorption of Na+ is attenuated during PPAR-alpha activation. Our results suggest that understanding the mechanisms involved in PPAR-alpha activation is an important factor for treating hypertension and could provide useful therapeutic agents for the treatment of end-stage renal disease. (End of Abstract)