The Role of PPAR-alpha during Angiotensin II Hypertension

PPAR-α 在血管紧张素 II 型高血压中的作用

• 批准号: 7822928
• 负责人: DEXTER L LEE
• 金额: $ 11.53万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-20 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822928
• 关键词: Adult; Angiotensin II; Attenuated; Blood Pressure; Chronic; Data; Development; End stage renal failure; Excretory function; Fenofibrate; Goals; Hormones; Hypertension; Hypotension; Inflammatory; Injury; Intake; Interleukin-6; Kidney; Knock-out; Knockout Mice; Ligands; Measurement; Mus; Nephrons; Nuclear; Oxidative Stress; PPAR alpha; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Plasma; Play; Production; Puncture procedure; Reporting; Risk; Role; Sodium; Superoxides; Techniques; Testing; Therapeutic Agents; United States; Wild Type Mouse; absorption; abstracting; blood pressure regulation; cytokine; effective therapy; mouse model; receptor; research study; response; tempol; transcription factor; urinary; Adult; Angiotensin II; Attenuated; Blood Pressure; Chronic; Data; Development; End stage renal failure; Excretory function; Fenofibrate; Goals; Hormones; Hypertension; Hypotension; Inflammatory; Injury; Intake; Interleukin-6; Kidney; Knock-out; Knockout Mice; Ligands; Measurement; Mus; Nephrons; Nuclear; Oxidative Stress; PPAR alpha; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Plasma; Play; Production; Puncture procedure; Reporting; Risk; Role; Sodium; Superoxides; Techniques; Testing; Therapeutic Agents; United States; Wild Type Mouse; absorption; abstracting; blood pressure regulation; cytokine; effective therapy; mouse model; receptor; research study; response; tempol; transcription factor; urinary

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)

描述（由申请人提供）： 在美国，每四个成年人中有一个患有高血压，并且有终末期肾脏疾病的风险增加。尽管在提供高血压的更有效治疗方面取得了长足的进步，但血压的慢性升高仍会导致进行性肾脏损害。最近的报道表明，促炎性细胞因子白介素6（IL-6）在肾脏损伤和慢性高血压中起着重要作用。过氧化物酶体增殖物激活受体（PPAR）-Alpha是一种核激素激活的受体和转录因子，抑制，IL-6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多。然而，PPAR-Alpha调节肾脏依赖性慢性高血压的机制并不理解。我们在慢性血管紧张素II（ANGLL）诱导的高血压的PPAR-Alpha敲除（KO）小鼠模型中介绍了新数据，与野生型（WT）对照相比，升压反应增加和血浆IL-6。我们的新发现表明，pPAR-α配体（fenodobibribriblet）降低了WT小鼠中对ANGLL和血浆IL-6的血压反应。在Angll + Fenodrate治疗过程中，与PPAR-Alpha KO小鼠相比，WT小鼠的尿Na +排泄率升高。因此，该提案的总体目标是确定PPAR-Alpha通过IL-6依赖途径降低慢性高血压的肾机制。我们将进行慢性血压测量结果，并利用单个肾单位微穿刺技术来测试中心假设，即PPAR-Alpha激活通过降低循环IL-6和Na+重新吸收近端小管中的循环IL-6和Na+重新吸收来降低慢性Angll诱导的高血压。在该提议中，三个具体目的是：1）检验以下假设：PPAR-Alpha激活通过IL-6依赖机制降低Angll诱导的高血压，2）确定导致PPAR-Alpha KO小鼠血压升高的机制 激活。我们的结果表明，了解PPAR-Alpha激活所涉及的机制是治疗高血压的重要因素，并且可以为治疗终末期肾脏疾病提供有用的治疗剂。 （抽象的结尾）