# Role of GPR56 in glomerular endothelial cell injury in early diabetic kidney disease

> **NIH NIH K01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $140,475

## Abstract

Glomerular endothelial cell (GEC) dysfunction is an early event in DKD which promotes the disease
progression. However, the mechanisms of GEC injury in DKD remain unclear. Thus, a better understanding of
the underlying processes of GEC injury is urgently required for the development of an early therapeutic
intervention. Recently, we developed a novel method of effective isolation of GECs from transgenic mice
expressing enhanced yellow fluorescent protein (EYFP) under the endothelium-specific Flk1 promoter (Fu J et
al. KI, 2018). We were able to sort GECs from these mice with or without DKD for RNA-seq. We also
performed single-cell RNA-seq of glomeruli isolated from these mice, which also allow us to compare the
transcriptome of GECs at the single cell level between diabetic and non-diabetic mice (Fu J et al. JASN, 2019).
From these studies, we found that many of the differentially expressed genes (DEGs) in diabetic GECs were
involved in the regulation of endothelial injury in early DKD. Among these, G-protein coupled receptor-56
(GPR56) was found to be highly upregulated in diabetic GECs. GPR56 codes for an atypical G protein-coupled
receptor and is also referred to as Adhesion G Protein-Coupled Receptor G1 (ADGRG1). Expression of
Collagen III, a major ligand for GPR56, is also accumulated in diabetic kidney. GPR56 activates mainly
G12/13-mediated RhoA-ROCK pathway, which is known to mediate endothelial cell dysfunction in DKD. Like
other adhesion receptors, GPR56 also responds to shear stress, which is increased in GECs of diabetic
kidneys due to glomerular hyperfiltration. Our key preliminary observations are: 1) Recent single-cell RNA-seq
data confirm that GPR56 expresses predominantly in GECs in the glomeruli. 2) Both mRNA and protein
expression of GPR56 increase in human DKD and correlate negatively with eGFR, suggesting an important
role of GPR56 in human DKD. 3) GPR56 is upregulated in cultured GECs by high glucose and advanced
glycation endproducts (AGE). 4) Collagen III treatment suppressed eNOS phosphorylation and expression
through activation of GPR56. 5) GPR56 reduces eNOS phosphorylation likely through G12/13-mediated RhoA
pathway and inhibits eNOS expression via Gi-mediated inhibition of cAMP/PKA/KLF4 pathway in cultured
mGECs. 6) Knockout of GPR56 enhances eNOS and KLF4 expression in GECs and attenuated albuminuria
and glomerular injury in mice with DKD. Based on these findings, we hypothesize that GPR56 mediates
disease progression in DKD by increasing GEC injury. We propose to determine the role and mechanism of
GPR56 signaling pathway in diabetes-induced GEC injury in vitro in GECs treated with diabetic condition and
in vivo in mice with DKD. We believe that our studies will help us to determine whether GPR56 could be a
potential new target to treat DKD by targeting GEC injury. The principal investigator will learn the skills and
new techniques under the guidance of her mentoring team (Drs. John He, Ravi Iyenger, Weijia Zhang, ...

## Key facts

- **NIH application ID:** 10214883
- **Project number:** 1K01DK125614-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jia Fu
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $140,475
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214883

## Citation

> US National Institutes of Health, RePORTER application 10214883, Role of GPR56 in glomerular endothelial cell injury in early diabetic kidney disease (1K01DK125614-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214883. Licensed CC0.

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