The Role of Vitamin D Deficiency-induced Macrophage Renin Angiotensin System Activation in the Development of Hypertension

RESEARCH STRATEGY: The objective of this proposal is to delineate the mechanisms by which macrophage renin signaling contributes to the development of hypertension (HTN) associated with disrupted vitamin D (VD) signaling. HTN is the most common chronic disease in the veteran population and associated with an increased

risk of cardiovascular disease and stroke. Despite our best efforts, many veterans have uncontrolled HTN, highlighting the need for novel therapeutic strategies. Since VD deficiency is common among veterans, associated with the development of HTN in humans, and promotes a pro-inflammatory macrophage phenotype,

we have focused on the mechanisms by which disrupted VD signaling contributes to the development of HTN. We have found that macrophage renin secretion is stimulated by deletion of the VD receptor (VDR) in macrophages (KODMAC). Transplantation of bone marrow from KODMAC mice into renin-null mice normalizes

blood pressure (BP) and restores circulating renin, highlighting the physiological relevance of macrophage renin in regulating systemic BP. However, the role of local macrophage renin in driving HTN, as well as the mechanisms governing macrophage renin transcription and the impact of macrophage-produced renin on

macrophage immune function are not known. The goal of this proposal is to test the hypothesis that macrophage renin is a critical non-renal modulator of systemic HTN and inflammation in the setting of disrupted VD signaling. Our Aims are to (1) determine the role of local macrophage renin in mediating the

development of HTN in murine models with disrupted macrophage VD signaling and (2) determine the mechanisms associated with macrophage renin upregulation in the setting of disrupted VD signaling and its effect on the macrophage function/secretome. The expected outcome of this work is to establish a new paradigm

by which impaired VD signaling functions as a major immunoregulatory program involved in systemic BP regulation via increase macrophage renin production. We also expect that these findings will generate novel therapeutic strategies for HTN management. CANDIDATE/ENVIRONMENT: Dr. Kevin Bauerle is a Staff Physician in Endocrinology at the St. Louis VAMC

and Instructor in Medicine within the Division of Endocrinology at Washington University (WU). He completed his M.D., Ph.D. training at the University of Colorado School of Medicine where he performed graduate studies in Dr. Bryan Haugen's laboratory. Dr. Bauerle completed his residency in internal medicine at Beth Israel

Deaconess Medical Center and endocrinology fellowship at WU. He conducted his fellowship research with Dr. Charles Harris, and currently works with his mentor Dr. Carlos Bernal-Mizrachi. Dr. Bauerle has gained experience in metabolic phenotyping and VD signaling in immune cells and developed novel mouse models to

investigate the role of macrophage renin signaling in HTN. He now seeks to expand his expertise in immunology, macrophage phenotyping, and cardiovascular phenotyping prior to starting his independent research career. CAREER DEVELOPMENT: This award will ensure that Dr. Bauerle is able to establish a career as an

independent physician scientist in the VA health care system. He has developed a formal 5-year training plan that will expand his scientific skills in immune cell biology and cardiometabolic phenotyping, as well as academic skills in scientific publishing, grant writing, and laboratory management. Dr. Bauerle's training will be

accomplished with experimental research, didactics, seminars, and national conferences. He has assembled a scientific advisory committee with the requisite experience and expertise to monitor and support his progress towards achieving his career goals. At the completion of the CDA-2, Dr. Bauerle will be equipped with a unique

skillset to prepare him for an independent career aimed at evaluating the role of nuclear hormone receptors in immune cells and endocrine tissues in promoting metabolic disease. He will be uniquely prepared to address fundamental questions that require knowledge of immunology, endocrinology, and cardiovascular disease.