The Renal Medulla and Hypertension

描述（由申请人提供）：本项目将检验中心假设，即肾髓质中HO-1的增加通过抑制血管紧张素II（Ang II）诱导的NADPH氧化酶和超氧化物生成的增加（经由胆红素和CO依赖性机制）来降低血管紧张素II（Ang II）高血压的血压。这将通过结合的综合生理学和体外方法来实现。该提议的具体目的是1）检验肾髓质HO-1水平的慢性降低增强和肾髓质HO-1的慢性诱导减弱Ang II介导的肾压-尿钠排泄和降低血压的钝化的假设，2）检验HO-1的慢性变化可以改变肾髓质中Ang II介导的NADPH氧化酶和超氧化物产生的增加的假设，3）为了检验HO-1代谢产物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增加中是必需的这一假设，4）为了检验HO-1水平的慢性增加（特别是在Henle的粗升袢（TALH）中）可以减少Ang II介导的肾压改变的假设，通过降低TALH中Ang II介导的NADPH氧化酶活性和超氧阴离子的产生来实现尿钠排泄和降低血压。该方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间质导管长期输注到接受Ang II长期输注的小鼠中。目的4中的实验将在新的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。该提议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间质导管长期输注到接受Ang II长期输注的小鼠中。进一步的研究将确定HO-1及其代谢产物，CO和胆红素，对血管紧张素II介导的超氧化物的生产中的作用，在孤立的小管节段和培养的细胞。本申请中提出的研究具有重要意义，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的血压提供新的见解。了解HO-1在肾髓质中的抗高血压作用的潜在机制可能为某些对当前治疗有抵抗力的高血压患者群体提供新的治疗选择。公共卫生相关性：本申请中提出的研究具有重要意义，因为它将为肾脏如何调节血压以及肾功能改变如何导致高血压或高血压的机制提供新的见解。更好地了解肾脏如何控制血压可能为开发新药物治疗对当前疗法有抵抗力的高血压患者提供机会。

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.