AT1 Angiotensin Receptors in the Renal Circulation Control Blood Pressure

项目摘要/摘要：这是VA BLR&D职业发展的首次重新提交申请 Award 2（CDA-2）建议对肾脏血管系统的作用进行彻底的研究。 循环在血压稳态和高血压发病机制中的作用。我是一个受过临床训练的 长期目标是了解高血压的基本机制的肾病学家。这 建议将通过促进扩大 将我的知识基础转化为需要在这些新领域进行指导的新的调查路线。的专门知识 导师协助这项赠款提案将是必不可少的成功完成这两个 该奖项的教育使命以及拟议的研究计划，跨越性能 这些地区托马斯科夫曼，医学博士，我的主要导师，有广泛的专业知识，在高血压 研究和肾素-血管紧张素系统;史蒂芬克劳利，医学博士，将提供专业知识，在肾交叉 移植和早期职业指导;苏珊格利，医学博士，博士将提供指导条件 小鼠中的基因靶向和肾上皮中钠转运蛋白的评估; Christopher 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， 从事临床医学和研究。此外，我将参加一个严格的职业生涯， 本申请中概述的发展计划将有助于确保成功 转型为独立研究者。项目总结：高血压是一种常见的 严重影响心血管健康的慢性疾病。用于拮抗 肾素-血管紧张素系统，如血管紧张素转化酶抑制剂和血管紧张素 受体阻滞剂有效降低血压， 并发症肾素-血管紧张素系统控制血压的作用主要是 由I型（AT 1）血管紧张素受体介导。然而，AT 1受体在多种细胞中表达， 参与血压调节的器官系统中的细胞类型（例如;脑，心脏，肾， 肾上腺和血管），并且不知道哪些细胞谱系和组织隔室 调解其影响。我们在缺乏AT 1受体的小鼠中进行的初步研究， 血管系统的肌肉细胞导致基础血压降低，并保护血管紧张素II- 诱发性高血压出乎意料的是，我们的发现表明血管紧张素II引起血管收缩， 通过对平滑肌细胞的直接作用和 交感神经系统的激活。然而，在肾循环中，血管紧张素II起作用， 几乎完全通过血管平滑肌细胞上的AT 1受体。基于这些 初步研究结果，我们假设血管AT 1受体有助于发病机制， 高血压主要是通过其在肾脏内的阻力血管中的作用，以减少肾小管周围的 血流量和减少尿钠排泄，从而促进血压升高。这 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测量。 生物学方法。我的方法使用了一种新的转基因小鼠模型， 交叉移植来回答关于血压稳态的基本问题。

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.