# Soluble (pro)renin receptor regulation of kidney fibrosis

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $433,541

## Abstract

ABSTRACT
 Chronic kidney disease (CKD) affects an estimated 37 million people in the United States.
CKD progression involves activation of inflammatory and fibrotic responses leading to irreversible
damage and loss of kidney function. The (pro)renin receptor (PRR) is implicated in the
pathogenesis of CKD and can exist as the full length form, bound to cell membrane or be cleaved
to generate a soluble PRR (sPRR) and M8.9 fragments. Although the function of the full-length
PRR both at a molecular and system level has been studied to some extent, the pathophysiologic
role of sPRR in CKD is unknown. This is especially important, since elevated plasma sPRR levels
have been described in patients with CKD and correlates with the stage of CKD. We recently
developed a novel mouse model with absence of sPRR using CRISPR-Cas9 directed
mutagenesis of the PRR cleavage site. Preliminary analyses show mutant sPRR mice have
reduced renal injury, inflammation and fibrosis compared to control mice and may involve
inflammatory signaling and oxidative phosphorylation pathways. The following specific aims will
be addressed:
 1. Investigate the pathophysiological role of sPRR in kidney disease. CKD will be induced in
 control and mutant sPRR mice using adenine diet or unilateral ureteral obstruction. Renal
 function, tubular injury, inflammation and fibrosis will be examined in conjunction with
 targeted comparative transcriptomics to identify active signaling pathways.
 2. Investigate the cellular mechanisms by which sPRR modulates kidney injury. sPRR
 regulation of inflammatory signaling pathways and oxidative phosphorylation and
 mitochondrial function will be examined in primary proximal tubule cell culture from control
 and mutant sPRR mice in presence of adenine or TGF-. Recombinant sPRR will be added
 to control and mutant cells lacking sPRR to examine if restoring sPRR levels reverses the
 renoprotective effects.
 3. Investigate the molecular interaction partners of sPRR. How sPRR mediates intracellular
 cell signaling will be examine by identifying protein-protein interactors through structure-
 guided affinity purification and mass-spectrometry and enzyme catalyzed proximity labeling
 in HEK293 cells. Mass spectrometry and proteomics analyses will delineate sPRR protein
 interaction and signaling under physiological conditions and in kidney disease.
 This proposal examines a novel modulator of kidney injury and fibrosis and will delineate the
mechanisms involved in mediating these effects. The integrative approach used herein will
identify systemic and molecular effects of sPRR in fibrosis and may help in the development of a
new therapeutic approach for CKD.

## Key facts

- **NIH application ID:** 10873819
- **Project number:** 5R01DK133271-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** NIRUPAMA RAMKUMAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,541
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873819

## Citation

> US National Institutes of Health, RePORTER application 10873819, Soluble (pro)renin receptor regulation of kidney fibrosis (5R01DK133271-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10873819. Licensed CC0.

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