Bilverdin Reductase, the Renal Medulla, and Hypertension

Bilverdin 还原酶、肾髓质和高血压

• 批准号: 8526644
• 负责人: Peter A Hosick
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-07-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526644
• 关键词: Acetates; Address; Adult; Affect; Alleles; Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Attenuated; Bilirubin; Biliverdin reductase; Biliverdine; Biochemical; Blood Pressure; Carbon Monoxide; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Culture Techniques; Cells; Chronic; Coronary Arteriosclerosis; Country; Data; Defect; Deoxycorticosterone; Development; Duct (organ) structure; End stage renal failure; Enzymes; Essential Hypertension; Excretory function; Experimental Animal Model; Functional disorder; Generations; Genetic; Genomics; Health; Heart Diseases; Heart failure; Heme; Henle' s loop; Human; Hypertension; Hypotension; Infusion procedures; Iron; Kidney; Kidney Diseases; Knock-out; Knowledge; Link; Measures; Mediating; Mentors; Mississippi; Modeling; Molecular; Mus; National Research Service Awards; Natriuresis; Oxidases; Oxidative Stress; Oxidoreductase; Oxygenases; Physiological; Physiology; Process; Production; Reactive Oxygen Species; Regulation; Renal function; Reporting; Research; Research Training; Resistance; Rest; Risk; Risk Factors; Role; Sodium; Sodium Chloride; Southeastern United States; Stroke; Superoxides; System; Techniques; Technology; Testing; Thick; Training; United States; Up-Regulation; Work; base; blood pressure regulation; cell type; clinically relevant; heme oxygenase-1; hypertension treatment; in vivo; insight; kidney medulla; mouse model; novel; novel therapeutics; patient population; pressure; public health relevance; research study; response

DESCRIPTION (provided by applicant): Previous research has demonstrated that kidney specific induction of heme oxygenase (HO)-1 can attenuate the development of hypertension; however, the specific role of biliverdin reductase (BVR) mediated bilirubin production to this effect has yet to be determined. Biliuribin is one of the most powerful antioxidants in the body. I not only can directly scavenge superoxide anion but it also has been reported to directly inhibit superoxide production through effects on NAD(P)H oxidases. Knockdown of BVR to a level which decreased the intracellular bilirubin generation by 50% was found to significantly increase angiotensin (Ang) II mediated superoxide production in cultured mouse thick ascending loop of Henle (TALH). This project will examine the role of intracellular bilirubin generation in the renal TALH and collecting duct (CD) in modulating renal-pressure natriuresis and blood pressure regulation. Conditional BVR knockout models developed using Cre-lox technology will be used to test the central hypothesis that intracellular bilirubin generation decreases reactive oxygen species (ROS), decreases sodium reabsorption in the TALH and CD through unique mechanisms, restores pressure natriuresis and lowers blood pressure in Ang II and deoxycorticosterone (DOCA)-salt hypertensive mice. To test this hypothesis a combination of whole animal integrative physiology as well as molecular, cellular, and genomic techniques will be used in both Ang II and DOCA-salt hypertensive mice. The research proposed is significant because it will provide new insights into the role of intracellular generated bilirubin in the TALH and CD in the regulation of renal pressure-natriuresis and the development of hypertension. These studies will be the first to specifically determine the role BVR in the regulation of renal pressure natriuresis and will provide an understanding of the role of bilirubin generation to the antihypertensive actions of HO-1 induction in the renal medulla. The results obtained from these studies will expand our knowledge about the function of BVR, the importance of intracellular bilirubin generation and could provide novel therapeutic options for certain hypertensive patient populations who are resistant to current therapies. In addition to increasing our knowledge of bilirubin action as a potential antihypertensive agent these studies will increase the applicant's understanding of whole animal integrative physiology as well as state of the art molecular, cellular, and genomic techniques. The specific role of BVR and intracellular bilirubin generation in the TALH and CD to ROS generation and blood pressure regulation will be addressed in two specific aims: 1. To test the hypothesis that chronic decreases in TALH or CD BVR exacerbates Ang II dependent hypertension via increases in Ang II mediated ROS which alters the renal pressure natriuresis relationship. 2. To test the hypothesis that chronic decreases in TALH or CD BVR exacerbates DOCA-salt dependent hypertension via increases in ROS which alters the renal pressure natriuresis relationship.

描述(申请人提供)：先前的研究表明，肾脏特异性地诱导血红素加氧酶(HO)-1可以减缓高血压的发展；然而，胆绿素还原酶(BVR)介导的胆红素产生的具体作用尚未确定。胆红素是人体内最强的抗氧化剂之一。I不仅能直接清除超氧阴离子，而且通过对NAD(P)H氧化酶的作用直接抑制超氧阴离子的产生。血管紧张素II(Ang II)介导的超氧化物歧化(O2)生成显著增加培养的小鼠粗大Henle升环(TALH)中超氧阴离子的产生。该项目将研究细胞内胆红素生成在肾脏中的作用。 TALH和集合管(CD)在调节肾压利钠和血压调节中的作用。使用Cre-lox技术开发的条件性BVR基因敲除模型将用于验证中心假设，即在Ang II和脱氧皮质酮(DOCA)-盐性高血压小鼠中，细胞内胆红素生成减少了活性氧(ROS)，通过独特的机制减少了TALH和CD中的钠重吸收，恢复了压力钠尿，并降低了血压。为了验证这一假设，将在Ang II和DOCA-SALT高血压小鼠中使用整体动物综合生理学以及分子、细胞和基因组技术的组合。提出的这项研究意义重大，因为它将为细胞内产生的胆红素在TALH中的作用提供新的见解 和Cd在肾压-钠尿调节和高血压的发生发展中的作用。这些研究将首次专门确定BVR在调节肾压力钠尿中的作用，并将提供对肾髓质HO-1诱导的降压作用中胆红素生成的作用的理解。这些研究的结果将扩大我们对BVR功能、细胞内胆红素生成的重要性的了解，并可能为某些对当前治疗方案产生抵抗力的高血压患者提供新的治疗选择。除了增加我们关于胆红素作为一种潜在的降压药的作用的知识外，这些研究还将增加申请者对整个动物综合生理学以及最先进的分子、细胞和基因组技术的了解。BVR和细胞内胆红素的生成在TALH和Cd对ROS的产生和血压调节中的具体作用将在两个特定的目的中得到解决：1.验证TALH或Cd BVR的慢性减少通过Ang II介导的ROS增加而加重Ang II依赖性高血压的假说，从而改变肾压钠尿关系。2.验证TALH或Cd BVR慢性降低通过增加ROS改变肾压钠尿关系而加重DOCA-盐依赖型高血压的假说。