# Pro/renin receptor-mediated signaling in pathogenesis of diabetic retinopathy

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $381,250

## Abstract

Project Summary:
A large body of experimental and clinical evidence has demonstrated that dysregulation of the
renin angiotensin system (RAS), resulting in elevated concentrations of Angiotensin II (Ang II),
contributes to increased inflammation, oxidative stress, and development of metabolic syndrome,
obesity, diabetes and its complications including DR. In addition to circulating RAS, components
of RAS are also expressed in different tissues including the eye. Local RAS dysfunction
contributes to tissue pathophysiology and end-organ damage in diabetes. However, the exact
mechanisms by which ocular RAS contribute to retinal pathophysiology in diabetes are still not
well-understood. Prorenin, a precursor of the active renin, the rate-limiting enzyme in RAS
cascade, is highly elevated plasma of diabetic patients and ocular fluid of DR patients. The
discovery of its receptor, pro/renin receptor (PRR), provided a mechanistic link of elevated
prorenin in pathogenesis of DR. Activation of this pathway has been shown to increase Ang II
production at tissue level, as well as direct activation of downstream signaling independent of Ang
II action, both of which contribute to end-organ damage. In addition to function as a crucial
component of RAS, PRR is an integral component of vacuolar H+-ATPase (V-ATPase), which
plays central roles in the acidification of intracellular compartments and cellular pH homeostasis.
PRR also acts an adaptor protein between the Wnt signaling complex and V-ATPase. Moreover,
a soluble form of PRR (sPRR) is produced by protease-mediated cleavage and is elevated under
various pathological conditions including DR. Increasing evidence implicates a pathological role
of elevated sPRR; however, the mechanisms by which sPRR contribute to pathogenesis of these
conditions are still not fully understood. We hypothesize that elevated prorenin, PRR and its
soluble form (sPRR) contribute to pathogenesis of DR by multiple pathways, leading to local RAS
activation, as well as signaling events independent of Ang II action. The goal of this proposal is
to (1) determine the mechanisms of prorenin-induced, PRR-mediated signaling pathways in
pathogenesis of DR; (2) determine whether elevated sPRR mediate prorenin-stimulated effects
and activates Ang II-dependent pathways in the retina; and (3) determine the effects and
mechanisms of prorenin and sPRR on V-ATPase function and associated cellular processes.
Collectively, the proposed studies will determine the mechanism(s) and signaling pathways by
which prorenin, pro/renin receptor, and its soluble form contribute to retinal neurovascular
dysfunction in diabetes. Knowledge of the mechanisms and relationship between these pathways
will drive the development of more effective therapies for diabetic retinopathy.

## Key facts

- **NIH application ID:** 10908720
- **Project number:** 5R01EY035413-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Qiuhong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908720

## Citation

> US National Institutes of Health, RePORTER application 10908720, Pro/renin receptor-mediated signaling in pathogenesis of diabetic retinopathy (5R01EY035413-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908720. Licensed CC0.

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