# (Pro)renin receptor regulates autophagy in diabetic kidney disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $405,000

## Abstract

Diabetic kidney disease (DKD) is the most common cause of end stage renal disease (ESRD) in both type 1
and type 2 diabetes. Impaired autophagy is implicated in the development of DKD. In this application, we
propose that increased (Pro)renin receptor (PRR) in diabetes, reduces autophagy in renal glomerular and
tubular cells leading to development of DKD. Our preliminary in vitro and in vivo studies demonstrated that
hyperglycemia increases PRR expression and activity, a process that is mediated by NFkB. Our data also
suggested that PRR contributes to the development of renal inflammation, fibrosis, and albuminuria. In renal
podocytes, mesangial, and inner medullary collecting duct cells, high-glucose-induced inhibition of SIRT1,
stimulation of mTOR and PKC-ROS, impaired autophagy and enhanced apoptosis. Reduction in renal PRR
expression reversed high glucose-induced intracellular signal abnormalities and improved autophagy. Based
on these data, it is likely that diabetes-induced increase in renal PRR expression impairs autophagy, leading to
cellular injury and directly contributes to development of DKD. The long-term goal of our research program is to
elucidate novel glomerular and tubular mechanisms that involve PRR and contribute to the development of
diabetes induced renal disease. To achieve this goal, we will utilize a rationale and novel integrated
approaches, consisting of in vivo studies utilizing a novel inducible nephron specific PRR knockdown mouse
model to manipulate tubular PRR and renal cortical interstitial administration of PRR shRNA to manipulate
glomerular and cortical tubules PRR. These studies will be complemented by state-of-the-art in vitro cellular
and molecular techniques including utilization of Laser scanning confocal microscopy. Based on our
preliminary data, the central hypothesis of this proposal is that increased renal PRR expression and activity
in diabetes contributes to development of renal tubular and glomerular inflammation, fibrosis, and
cellular apoptosis by inhibiting autophagy via stimulation of SIRT1-FoxO3, PI3K-Akt-mTOR and PKC-
ROS signaling pathways (Figure 1). In this proposal, we will pursue the following specific aims:
Aim 1: To test the hypothesis that renal tubular PRR contributes to development of DKD by inhibiting SIRT1-
FoxO3a-autophagy pathway, leading to tubular fibrosis and apoptosis. Aim 2: To test the hypothesis that PRR
contributes to glomerular injury in diabetes by enhancing PI3K-AKT-mTOR signaling pathway in renal
mesangial cells (RMCs) and podocytes, leading to reduction in autophagy activity, inflammation, increased
matrix formation, and apoptosis. Aim 3: To test the hypothesis that PRR contributes to the development of
DKD by stimulating PKC-NOX4-NFkB signaling pathway activity and inhibiting autophagy leading to enhanced
renal inflammation, fibrosis and apoptosis.
These studies are expected to identify novel mechanisms that contribute to development of DKD. These
mechanisms could le...

## Key facts

- **NIH application ID:** 9952401
- **Project number:** 5R01HL091535-18
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Helmy M Siragy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2008-01-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952401

## Citation

> US National Institutes of Health, RePORTER application 9952401, (Pro)renin receptor regulates autophagy in diabetic kidney disease (5R01HL091535-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952401. Licensed CC0.

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