The Renal Medulla and Hypertension

描述(申请人提供)：该项目将测试中心假设，即增加肾髓质HO-1可通过抑制Ang II通过胆红素和一氧化碳依赖机制诱导的NADPH氧化酶和超氧化物生成增加，从而降低Ang II高血压患者的血压。这将通过综合的生理和体外方法来实现。这一建议的具体目的是：1)检验慢性降低肾髓质HO-1水平增强和慢性诱导肾髓质HO-1减轻Ang II介导的肾压-钠尿钝化和血压降低的假说；2)检验HO-1的慢性变化可以改变Ang II介导的肾髓质NADPH氧化酶和超氧化物生成增加的假说；3)检验HO-1代谢物CO和胆红素在缓冲Ang II介导的NADPH氧化酶、超氧化物生成和血压增加中必不可少的假说。4)验证慢性升高HO-1水平的假说，尤其是在粗大的Henle升环(TALH)，可以通过减少Ang II介导的NADPH氧化酶活性和超氧阴离子产生来减轻Ang II介导的肾压-钠排泄改变，从而降低血压。这项建议中的实验将在小鼠身上进行，在小鼠中，HO-1的HO抑制剂和诱导剂将通过肾内髓质间质导管慢性注入接受Ang II的小鼠。AIM 4中的实验将在一种新的转基因小鼠模型上进行，在该模型中，人HO-1亚型在TALH细胞中特异表达。这项建议中的实验将在小鼠身上进行，在小鼠中，HO抑制剂或诱导剂将通过肾髓质内导管慢性注入接受Ang II的小鼠。进一步的研究将确定HO-1及其代谢物CO和胆红素对Ang II介导的体外肾小管段和培养细胞产生超氧化物的作用。这项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的诱导如何降低高血压患者的氧化应激和降压机制提供新的见解。了解肾髓质中HO-1抗高血压作用的机制可能会为某些对现有治疗方法有抵抗力的高血压患者提供新的治疗选择。公共卫生相关性：这项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变化如何导致高血压或高血压提供新的见解。更好地了解肾脏是如何控制血压的，可能会为开发新药来治疗对当前疗法产生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.