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.
Hypertension is a major contributor to heart disease, stroke and kidney disease and is the most common medical condition among veterans. This proposal explores how angiotensin receptors in vascular smooth muscle contribute to end-organ damage related to hypertension and how these receptors contribute to blood pressure regulation. Furthermore, this proposal will help to answer fundamental questions about how the blood flow to the kidney is regulated by the renin angiotensin system. New discoveries in this area should provide insights into the causes of high blood pressure and associated tissue damage, and may lead to more effective strategies for treatment of high blood pressure in veterans.
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