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）：该项目将测试肾脏髓质中HO-1增加的中心假设，可通过抑制ANG II诱导的NADPH氧化酶和超氧化物通过Billirubin和CO依赖机制抑制ANG II诱导的NADPH氧化酶和超氧化物的产生，从而降低血管紧张素II（ANG II）高血压的血压。这将通过联合整合生理和体外方法来实现。该提案的具体目的是1）检验以下假说：肾脏髓质HO-1水平的慢性降低增强和慢性诱导肾脏髓质HO-1的减弱，肾脏II介导的ANG II介导的肾压力 - 肾上腺素和降低血液压力，降低血液压力，2）测试HO-1中的慢性变化可以改变HOS的氧化变化。 3）测试HO-1代谢物CO和胆红素在缓冲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的假设，4），4），以下假设，即HO-1水平的慢性在HENLE（TALH）较厚的henle（TALH）中的慢性降低（TALH）中的较高趋势降低了肾脏压力降低，并降低了肾脏压力降低的降低，而肾脏降低了血压的降低。 TALH中的活性和超氧化阴离子的产生。该提案中的实验将在小鼠中进行，其中HO-1的HO抑制剂和诱导剂将通过肾上腺内髓质性导管在接受ANG II的慢性输注的小鼠中长期注入。 AIM 4中的实验将在新型的转基因小鼠模型上进行，其中人HO-1同工型在TALH细胞中特异性表达。该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接受ANG II的慢性输注的小鼠中的肾内髓质间质导管长期注入。进一步的研究将确定HO-1及其代谢产物CO和胆红素对分离的小管片段和培养细胞中ANG II介导的超氧化物产生的作用。在本应用中提出的研究很重要，因为它将为肾脏髓质中HO-1诱导如何减少氧化应激和降低高血压中的血压降低的机制提供新的见解。了解HO-1在肾脏髓质中抗高血压作用的机制可能为某些对当前疗法有抵抗力的高血压患者人群提供新的治疗选择。公共卫生相关性：本应用中提出的研究很重要，因为它将提供有关肾脏如何调节血压以及肾功能的变化如何导致高血压或高血压的机制的新见解。更好地了解肾脏如何控制血压的方式可能会为开发新药物治疗患有对当前疗法的高血压患者的机会。