The renin-angiotensin-system (RAS) plays a central role in regulating systemic blood pressure. This is illustrated by the proven benefit of RAS-targeted drugs such as angiotensin receptor blockers, which are critical to the treatment of hypertension, heart failure and kidney disease. The actions of the RAS depend on the peptide angiotensin II (ang II) acting on cells that express the G-protein coupled type 1 angiotensin receptor (human: AT1; mouse: AT1a). Our group has been at the forefront of unmasking cell-specific roles of ang II signaling within different cell populations in the kidney. These studies have revealed novel roles for ang II to act distinctly in different cell types to drive pathogenic mechanisms associated with hypertension. This suggests that the overall, systemic effect of ang II on blood pressure results from the cumulative actions of ang II on multiple cell types within the body. Our preliminary studies analyzed recently published single-cell RNA Sequencing datasets to explore the cell-specific expression of angiotensin receptors within the kidney. We find that pericytes, a mural cell type associated with capillaries and the glomerulus, express the mouse AT1a receptor. Additionally, we confirmed this by measuring AT1a expression from rapidly sorted pericytes from the kidney. However, the role of angiotensin signaling in pericytes remains under-examined. This is despite multiple lines of evidence that suggest renal pericytes play a central role in regulating blood pressure and renal injury, angiotensin-linked processes which are pathologically altered in hypertension and chronic kidney disease. This project will test the overall hypothesis that angiotensin II signaling within pericytes contributes to the development of hypertension and renal injury. This candidate has developed a novel mouse line which has inducible pericyte-specific deletion of the AT1a receptor. First, the contribution of pericyte ang II signaling to blood pressure control will be determined under baseline conditions and during ang II hypertension. Next, the effect of ang II signaling within pericytes on renal injury in the context of hypertension will be assessed. This research will be carried out by an applicant with excellent training in biomedical research with a strong publication record. The training for this proposal will occur at Oregon Health & Science University within the Division of Nephrology and Hypertension under the primary mentorship of Dr. Susan Gurley a leader in the field of cell-specific actions of RAS signaling in the kidney. This project will also be supported by two other co-mentors: Dr. Anusha Mishra, an expert on pericyte biology and microvascular blood flow, and Dr. Lynne Sakai, an expert on vascular fibrotic signaling. Career development activities include training in mouse micro-surgery, ex vivo slice imaging, assessment of renal pathology, and bioinformatic analysis of single-cell RNA sequencing datasets. This training is designed to launch the candidate to lead the next generation of kidney research with well-honed skills in animal physiology and molecular biology. This will setup the candidate to meet his long-term career coal of becoming an independent investigator focusing on the cellular and molecular causes of hypertension and renal injury.
Renal pericytes are the mural cell type associated with capillaries and express the major receptor for angiotensin II, a key vasoactive peptide of the renin-angiotensin system. However, the contributions of angiotensin II signaling in pericytes to regulate blood pressure are unknown. This project will use a novel mouse line with cell- specific deletion of type 1 angiotensin receptors in pericytes to examine the role of angiotensin II signaling in this specialized cell population to drive hypertension and renal injury.
