AT1 Angiotensin Receptors in the Renal Circulation Control Blood Pressure

AT1 血管紧张素受体在肾循环中控制血压

• 批准号: 8974347
• 负责人: Matthew Aaron Sparks
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974347
• 关键词: Adrenal Glands; Affect; Angiotensin I; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Applications Grants; Area; Attenuated; Award; Biological Preservation; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Brain; Cardiovascular system; Cell Lineage; Chronic; Clinical Medicine; Clinical Research; Cre-LoxP; Development; Development Plans; Doctor of Philosophy; Ensure; Epithelial; Epithelial Cells; Equilibrium; Excretory function; Gene Targeting; Genetic study; Goals; Health; Heart; Heart Diseases; Human; Hypertension; Hypotension; Immunoblotting; Investigation; K-Series Research Career Programs; Kidney; Kidney Diseases; Laboratories; Lead; Measurement; Measures; Mediating; Medical; Mentors; Mentorship; Mission; Molecular; Molecular Biology; Mus; Natriuresis; Nephrons; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Performance; Peripheral Resistance; Pharmaceutical Preparations; Physiological; Receptor, Angiotensin, Type 1; Renal Blood Flow; Renal Circulation; Renal function; Renin-Angiotensin System; Research; Research Personnel; Resistance; Role; Smooth Muscle Myocytes; Sodium; Stroke; Surveys; Sympathetic Nervous System; Technology; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Transplantation; Vascular Smooth Muscle; Vasoconstrictor Agents; Veterans; Vocational Guidance; Wild Type Mouse; Work; abstracting; attenuation; base; blood pressure reduction; blood pressure regulation; body system; cardiovascular health; career; career development; cell type; defined contribution; effective therapy; experience; improved; in vivo; innovation; insight; kidney vascular structure; knowledge base; mouse model; novel; pressure; receptor; renal epithelium; response; success; therapeutic target; treatment strategy; urinary; vascular contributions; vasoconstriction

DESCRIPTION (provided by applicant): Project Summary/Abstract: This first resubmission application for a VA BLR&D Career Development Award 2 (CDA-2) proposes a thorough investigation into the role of the vasculature in the renal circulation in blood pressure homeostasis and hypertension pathogenesis. I am a clinically trained nephrologist whose long-term goal is to understanding the basic mechanisms of hypertension. This proposal will fulfill the educational objective of the development award by facilitating the expansion of my knowledge base into novel lines of inquiry requiring mentorship in these new areas. The expertise of the mentors assisting in this grant proposal will be essential to the successful completion of both the educational mission of the award as well as the performance of the proposed research plan that spans these areas. Thomas Coffman, MD, my primary mentor, has extensive expertise in hypertension research and the renin-angiotensin system; Steven Crowley, MD, will provide expertise in kidney cross transplantation and early career guidance; Susan Gurley, MD, PhD will provide guidance on conditional gene targeting in mice and assessment of sodium transporters in renal epithelia; Christopher Kontos, MD, will provide expertise in endothelial activity and will provide critical mentorship on balancing careers in clinical medicine and research. Additionally, I will participate in a rigorous career development plan as outlined in this application that will be instrumental in ensuring the successful transition to being an independent researcher. PROJECT SUMMARY: Hypertension is a common chronic medical condition significantly impacting cardiovascular health. Medications used to antagonize the renin-angiotensin system, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers effectively reduce blood pressure and uniquely ameliorate cardiovascular complications. The actions of the renin-angiotensin system to control blood pressure are primarily mediated by the type I (AT1) angiotensin receptor. However, AT1 receptors are expressed in multiple cell types in organ systems involved in blood pressure regulation (for example; the brain, heart, kidney, adrenal gland, and blood vessels) and it is not known which cells lineages and tissue compartments mediate their effects. Our preliminary studies in mice lacking AT1 receptors specifically in smooth muscle cells of the vasculature resulted in reduced basal blood pressure and protection from Ang II- induced hypertension. Unexpectedly, our findings suggest that Angiotensin II causes vasoconstriction in the systemic circulation through a combination of direct actions on smooth muscle cells and activation of the sympathetic nervous system. However, in the renal circulation Angiotensin II acts almost exclusively through AT1 receptors on smooth muscle cells of the vasculature. Based on these preliminary findings, we hypothesize that vascular AT1 receptors contribute to the pathogenesis of hypertension primarily by their actions in resistance vessels within the kidney to reduce peritubular blood flow and decrease urinary excretion of sodium, thereby promoting increased blood pressure. This proposed work is innovative, in that it combines physiological measurements in mice with molecular biology approaches. My approach uses a combination novel transgenic mouse models with kidney cross transplantation to answer fundamental questions about blood pressure homeostasis.

描述（由申请人提供）： 项目概要/摘要：这是VA BLR&D职业发展奖2（CDA-2）的首次重新提交申请，提出了对肾循环中血管系统在血压稳态和高血压发病机制中的作用进行彻底调查。我是一名经过临床训练的肾病学家，其长期目标是了解高血压的基本机制。这项建议将通过促进我的知识基础扩展到需要在这些新领域进行指导的新的调查路线，实现发展奖的教育目标。导师的专业知识，协助这项赠款提案将是必不可少的成功完成两个教育使命的奖项，以及拟议的研究计划，跨越这些领域的表现。托马斯科夫曼，医学博士，我的主要导师，在高血压研究和肾素-血管紧张素系统方面具有广泛的专业知识;史蒂文克劳利，医学博士，将提供肾交叉移植和早期职业指导方面的专业知识;苏珊格利，医学博士，博士将提供小鼠条件基因靶向和肾上皮钠转运蛋白评估方面的指导;克里斯托弗Kontos，医学博士，将提供内皮活动的专业知识，并将提供关键的指导，平衡职业生涯在临床医学和研究。此外，我将参加 在严格的职业发展计划中概述了本申请，这将有助于确保成功过渡到成为一名独立的研究人员。项目总结：高血压是一种常见的慢性疾病，严重影响心血管健康。用于拮抗肾素-血管紧张素系统的药物，如血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂，可有效降低血压，并独特地改善心血管并发症。肾素-血管紧张素系统控制血压的作用主要由I型（AT 1）血管紧张素受体介导。然而，AT 1受体在参与血压调节的器官系统（例如，脑、心脏、肾、肾上腺和血管）中的多种细胞类型中表达，并且尚不知道哪些细胞谱系和组织隔室介导其作用。我们在缺乏血管平滑肌细胞特异性AT 1受体的小鼠中进行的初步研究导致基础血压降低和对Ang II诱导的高血压的保护。出乎意料的是，我们的研究结果表明，血管紧张素II通过对平滑肌细胞的直接作用和交感神经系统的激活的组合引起体循环中的血管收缩。然而，在肾循环中，血管紧张素II几乎仅通过血管平滑肌细胞上的AT 1受体起作用。基于这些初步研究结果，我们推测血管AT 1受体主要通过其在肾脏内阻力血管中的作用减少肾小管周围血流量和减少尿钠排泄，从而促进血压升高，从而促进高血压的发病机制。这项拟议的工作是创新的，因为它结合了小鼠的生理测量与分子生物学方法。我的方法使用一种新的转基因小鼠模型与肾脏交叉移植相结合，以回答有关血压稳态的基本问题。