AT1 Angiotensin Receptors in the Renal Circulation Control Blood Pressure

描述(由申请人提供)： 项目摘要/摘要：这是退伍军人管理局BLR&D职业发展奖2(CDA-2)的首次重新提交申请，旨在深入研究肾循环中的血管系统在血压稳态和高血压发病机制中的作用。我是一名受过临床训练的肾科医生，其长期目标是了解高血压的基本机制。这项提议将实现发展奖的教育目标，促进我的知识基础扩大到需要在这些新领域进行指导的新的调查路线。协助这一赠款提案的导师的专业知识对于顺利完成该奖项的教育使命以及执行跨越这些领域的拟议研究计划都是至关重要的。我的主要导师Thomas Coffman医学博士在高血压研究和肾素-血管紧张素系统方面拥有丰富的专业知识；Steven Crowley医学博士将提供肾脏交叉移植和早期职业指导方面的专业知识；Susan Gurley医学博士将提供小鼠条件性基因靶向和肾上皮钠转运蛋白评估的指导；Christopher Kontos医学博士将提供内皮活性方面的专业知识，并将提供平衡临床医学和研究职业的关键导师。另外，我也会参加 在本申请书中概述的严格的职业发展计划中，这将有助于确保成功过渡到独立研究人员。项目简介：高血压是一种常见的慢性疾病，严重影响心血管健康。用来对抗肾素-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，有效地降低血压，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(AT1)血管紧张素受体介导。然而，AT1受体在参与血压调节的器官系统(例如，脑、心脏、肾脏、肾上腺和血管)中表达多种类型的细胞，目前尚不清楚哪些细胞系和组织隔间介导了它们的作用。我们在血管平滑肌细胞中缺乏AT1受体的小鼠的初步研究结果表明，基础血压降低，对Ang II诱导的高血压具有保护作用。出乎意料的是，我们的发现表明，血管紧张素II通过直接作用于平滑肌细胞和激活交感神经系统，在全身循环中引起血管收缩。然而，在肾脏循环中，血管紧张素II几乎完全通过血管平滑肌细胞上的AT1受体起作用。根据这些初步发现，我们推测血管AT1受体主要通过作用于肾脏内的阻力血管，减少肾小管周围血流量，减少尿钠排泄，从而促进血压升高，从而参与高血压的发病。这项拟议的工作是创新的，因为它结合了小鼠的生理测量和分子生物学方法。我的方法使用了一种新的转基因小鼠模型和肾脏交叉移植相结合的方法来回答关于血压动态平衡的基本问题。

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.