The Renal Medulla and Hypertension

肾髓质和高血压

基本信息

批准号：
8316332
负责人：
DAVID E STEC
金额：
$ 32.97万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316332
关键词：
Address Angiotensin II Animals Antihypertensive Agents Attenuated Bilirubin Biliverdin reductase Biliverdine Blood Pressure Buffers Carbon Monoxide Catheters Cells Chronic Cultured Cells Diet Duct (organ) structure Enzymes Generations Genomics Gunn Rats Health Heme Henle&apos s loop Human Hypertension Hypotension In Vitro Inbred SHR Rats Individual Infusion procedures Iron Kidney Laboratories Lead Mediating Molecular Mus NADPH Oxidase Natriuresis Nitric Oxide Oxidases Oxidative Stress Oxygenases Pathogenesis Pharmaceutical Preparations Physiological Physiology Play Production Protein Isoforms Reactive Oxygen Species Renal Hypertension Renal Tissue Renal function Renovascular Hypertension Research Resistance Role Sodium Superoxides Techniques Testing Thick Transgenic Mice base blood pressure regulation feeding heme oxygenase-1 inhibitor/antagonist insight interstitial kidney medulla mouse model novel novel therapeutics patient population pressure research study

项目摘要

DESCRIPTION (provided by applicant): This project will test the central hypothesis that increased HO-1 in the renal medulla lowers blood pressure in angiotensin II (Ang II) hypertension by inhibiting Ang II induced increases in NADPH oxidase and superoxide production via billirubin and CO dependent mechanisms. This will be accomplished by a combined integrative physiological and in vitro approach. The specific aims of this proposal are 1) To test the hypothesis that chronic decreases in renal medullary HO-1 levels enhance and chronic induction of renal medullary HO-1 attenuates Ang II mediated blunting of renal pressure- natriuresis and lower blood pressure, 2) To test the hypothesis that chronic changes in HO-1 can alter the Ang II mediated increase in NADPH oxidase and superoxide production in the renal medulla, 3) To test the hypothesis that HO-1 metabolites CO and bilirubin are essential in buffering Ang II mediated increases in NADPH oxidase, superoxide production and blood pressure, 4) To test the hypothesis that chronic increases in HO-1 levels specifically in the thick ascending loop of Henle (TALH) can reduce Ang II mediated alterations in renal pressure-natriuresis and lower blood pressure via decreasing Ang II mediated NADPH oxidase activity and superoxide anion production in the TALH. Experiments in this proposal will be performed in mice in which HO inhibitors and inducers of HO-1 will be chronically infused via intrarenal medullary interstitial catheters in mice receiving chronic infusions of Ang II. Experiments in Aim 4 will be conducted on a novel transgenic mouse model in which the human HO-1 isoform is specifically expressed in TALH cells. Experiments in this proposal will be performed in mice in which HO inhibitors or inducers will be chronically infused via intrarenal medullary interstitial catheters in mice receiving chronic infusions of Ang II. Further studies will determine the role of HO-1 and its metabolites, CO and bilirubin, on Ang II-mediated superoxide production in isolated tubule segments and cultured cells. The research proposed in this application is significant because it will provide new insights into the mechanism of how induction of HO-1 in the renal medulla can reduce oxidative stress and lower blood pressure in hypertension. Understanding of the mechanisms underlying the anti-hypertensive actions of HO-1 in the renal medulla may provide novel therapeutic options for certain hypertensive patient populations which are resistant to current therapies. PUBLIC HEALTH RELEVANCE: The research proposed in this application is significant because it will provide new insights into the mechanism of how the kidney can regulate blood pressure and how alterations in kidney function can lead to high blood pressure or hypertension. A better understanding of the how the kidney controls blood pressure may provide an opportunity to develop new drugs to treat people with hypertension who are resistant to current therapies.

描述（由申请人提供）：该项目将测试核心假设，即肾髓质中 HO-1 的增加可通过抑制 Ang II 通过胆红素和 CO 诱导的 NADPH 氧化酶和超氧化物产生的增加来降低血管紧张素 II (Ang II) 高血压患者的血压依赖机制。这将通过综合生理学和体外方法相结合来实现。该提案的具体目的是 1) 检验以下假设：肾髓质 HO-1 水平的慢性降低会增强肾髓质 HO-1 水平，而肾髓质 HO-1 的长期诱导会减弱 Ang II 介导的肾压减弱 - 尿钠排泄和降低血压，2)为了检验 HO-1 的慢性变化可以改变 Ang II 介导的肾髓质 NADPH 氧化酶和超氧化物产生增加的假设，3) 检验以下假设： HO-1 代谢物 CO 和胆红素对于缓冲 Ang II 介导的 NADPH 氧化酶、超氧化物产生和血压的增加至关重要，4) 检验 HO-1 水平长期增加的假设，特别是在厚厚的亨利升袢 (TALH) 中可以通过降低 Ang II 介导的 NADPH 氧化酶活性和 TALH 中超氧阴离子的产生来减少 Ang II 介导的肾压尿钠排泄变化并降低血压。本提案中的实验将在小鼠中进行，其中 HO 抑制剂和 HO-1 诱导剂将通过肾内髓质间质导管长期输注到接受长期输注 Ang II 的小鼠中。目标 4 中的实验将在新型转基因小鼠模型上进行，其中人 HO-1 同种型在 TALH 细胞中特异性表达。本提案中的实验将在小鼠中进行，其中 HO 抑制剂或诱导剂将通过肾内髓质间质导管长期输注到接受长期输注 Ang II 的小鼠中。进一步的研究将确定 HO-1 及其代谢物 CO 和胆红素对离体肾小管段和培养细胞中 Ang II 介导的超氧化物产生的作用。本申请中提出的研究意义重大，因为它将为肾髓质中HO-1的诱导如何减少氧化应激和降低高血压患者的血压的机制提供新的见解。了解 HO-1 在肾髓质中抗高血压作用的机制可能为某些对现有疗法有抵抗力的高血压患者群体提供新的治疗选择。公共健康相关性：本申请中提出的研究意义重大，因为它将为肾脏如何调节血压的机制以及肾功能的改变如何导致高血压或高血压提供新的见解。更好地了解肾脏如何控制血压可能会提供一个机会来开发新药来治疗对现有疗法有抵抗力的高血压患者。