The Renal Medulla and Hypertension

描述（由申请人提供）：本项目将测试中心假设，即肾髓质中HO-1的增加通过抑制Ang II诱导的NADPH氧化酶和超氧化物产生的增加，通过台球红素和CO依赖机制，降低血管紧张素II （Ang II）高血压患者的血压。这将通过综合生理和体外方法来完成。本研究的具体目的是：1)验证肾髓质HO-1水平的慢性降低可增强和慢性诱导肾髓质HO-1可减弱Ang II介导的肾压钠尿和低血压的钝化；2)验证HO-1的慢性改变可改变Ang II介导的肾髓质NADPH氧化酶和超氧化物生成的增加的假设。3)验证HO-1代谢产物CO和胆红素在缓冲Ang II介导的NADPH氧化酶、超氧化物生成和血压升高中所必需的假说。4)验证慢性升高HO-1水平，特别是在Henle厚升环（TALH）中，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，可以减少Ang II介导的肾压-尿钠和血压降低的改变。本实验将在小鼠中进行，在接受慢性输注Ang II的小鼠中，通过肾内髓间质导管慢性输注HO-1抑制剂和HO-1诱导剂。Aim 4的实验将在一种新的转基因小鼠模型上进行，其中人类HO-1亚型在TALH细胞中特异性表达。本实验将在小鼠中进行，在小鼠中，HO抑制剂或诱导剂将通过肾内髓质间质导管长期输注于长期输注Ang II的小鼠。进一步的研究将确定HO-1及其代谢产物CO和胆红素在分离小管段和培养细胞中Ang ii介导的超氧化物产生中的作用。本应用提出的研究具有重要意义，因为它将为高血压患者诱导肾髓质HO-1减少氧化应激和降低血压的机制提供新的见解。了解肾髓质中HO-1抗高血压作用的机制可能为某些对现有治疗方法有耐药性的高血压患者群体提供新的治疗选择。公共卫生相关性：本应用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的机制以及肾脏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为开发新药提供机会，以治疗对现有疗法有抗药性的高血压患者。

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.