# Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem

> **NIH NIH K01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $112,479

## Abstract

PROJECT SUMMARY/ABSTRACT
 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.

## Key facts

- **NIH application ID:** 10242847
- **Project number:** 5K01HL153101-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Pablo Nakagawa
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $112,479
- **Award type:** 5
- **Project period:** 2020-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242847

## Citation

> US National Institutes of Health, RePORTER application 10242847, Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem (5K01HL153101-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242847. Licensed CC0.

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