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，并且患终末期肾病的风险增加。尽管在提供更有效的高血压治疗方面已经取得了很大的进步，但血压的慢性升高仍然会导致进行性肾损伤。最近的研究表明，促炎细胞因子白细胞介素-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-alpha）是一种核膜激活的受体和转录因子，其抑制IL-6的产生、氧化应激，并与血压调节有关。在肾脏中，PPAR-alpha在肾单位的近端小管段中表达最丰富。然而，PPAR-alpha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-alpha基因敲除（KO）小鼠慢性血管紧张素II（AngII）诱导的高血压模型中提供了新的数据，与野生型（WT）对照相比，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-alpha配体非诺贝特降低WT小鼠对AngII和血浆IL-6的血压反应。在AngII+非诺贝特治疗期间，当与PPAR-alpha KO小鼠相比时，WT小鼠中的尿Na+排泄升高。因此，本提案的总体目标是确定PPAR-alpha通过IL-6依赖性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技术来测试PPAR-alpha激活通过减少近端小管中的循环IL-6和Na+重吸收来减少慢性AngII诱导的高血压的中心假设。在该提议中，制定了三个具体目的：1）检验PPAR-a活化通过IL-6依赖性机制降低AngII诱导的高血压的假设，2）确定在AngII治疗期间PPAR-a KO小鼠中血压升高的机制，3）检验Na+的近端小管重吸收在PPAR-a活化期间减弱的假设。我们的研究结果表明，了解PPAR-alpha激活的机制是治疗高血压的一个重要因素，并可能为终末期肾病的治疗提供有用的治疗药物。(End摘要）

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)