Hypertension affects nearly half of the population and it is the principal risk factor for heart attack and stroke, the leading first and third cause of death in the United States. The renin-angiotensin system (RAS), is one of the most studied mechanisms of blood pressure control. The classical view of the RAS involves a sequential cleavage of the substrate angiotensinogen resulting in the elevation of circulating angiotensin II (ANG). In addition to functioning within the circulation as a classical (endocrine) hormone system, several tissues including the brain produce local acting ANG, supporting the concept that autocrine/paracrine/intracrine versions of the RAS act locally within these tissues. However, this scientific premise has been challenged due to the difficulties to detect renin in extrarenal organs. Indeed, the enzymes catalyzing the hydrolytic removal of the prosegment, which is required for the activation of renin, are absent in extrarenal tissues. Utilizing cutting edge molecular techniques with superior specificity and sensitivity we were able to identify specific cells located in the rostral ventrolateral medulla (RVLM) that express renin. We also observed that in a model of neurogenic hypertension, such as mice lacking the alternative renin isoform (renin-b), there is a disinhibition of the classical renin isoform (renin-a) encoding preprorenin within the RVLM. This data has been our driving force to interrogate what is the function of renin- expressing cells within the RVLM, and moreover, are these cells initiating ANG signaling within the areas adjacent to the RVLM by secreting prorenin to the extracellular space which is abundant of angiotensinogen? A key step to answer these questions is to decipher how prorenin is activated. The discovery of prorenin receptor (PRR), a receptor that binds prorenin and induces its activation without the cleavage of the prosegment, might be a key player to solve this problem. In the recent years, several ANG-independent and (pro)renin-independent functions of PRR have been demonstrated. Since then, the role of PRR mediating the local activation of the RAS has been questioned. Given the long-held controversy in this field, our fundamental goal is to clarify the physiological and molecular role of PRR within the RVLM and then to dissociate the actions that are dependent of the RAS versus those that are independent of the generation of ANG. Finally, we propose a transcriptomic approach to identify the neuronal and molecular signature of the renin-expressing cells within the RVLM. Collectively, this project will facilitate continued technical, intellectual, and professional training for the candidate, and assist in the establishment of an independent research laboratory at an academic research institution.
We have identified a cell population expressing renin within the rostral ventrolateral medulla (RVLM), a brainstem region involved in sympathetic control. The goal of this proposal is to elucidate the requirement of the prorenin receptor for the non-hydrolytic activation of prorenin within the RVLM. We also hypothesize that conditional ablation of prorenin receptor in the RVLM attenuates the manifestation of the cardiovascular abnormalities due to brain renin angiotensin system activation.
