Abstract: PO0660
Role of GRP56 in Glomerular Endothelial Cell Injury in Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - I
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Group or Team Name
- He Lab
Background
GEC injury is a key pathogenic event in early Diabetic kidney disease (DKD). However, the mechanisms of GEC injury in DKD remain unclear and the treatments by targeting specifically GEC injury are lacking.
Methods
By taking advantage of transgenic mice expressing enhanced yellow fluorescent protein (EYFP) under the endothelium-specific Flk1 promoter, we were able to sort GECs from both control and diabetic mice for RNA sequencing. We identified G-protein coupled receptor-56 (GPR56) as a highly upregulated gene in diabetic GECs. Then, we confirmed the role of GRP56 in GEC injury in DKD by both in vitro and in vivo studies.
Results
We searched the recent single-cell RNA-seq data and confirmed that GPR56 expresses predominantly in GECs in the glomeruli. We found that both mRNA and protein expression of GPR56 increased in human DKD and correlated negatively with eGFR, suggesting an important role of GPR56 in human DKD. In cultured GECs, GRP56 expression was upregulated by high glucose and advanced glycation endproducts (AGE). Collagen III, a major ligand of GPR56, was able to suppress eNOS phosphorylation and expression through activation of GPR56. We demonstrated that GPR56 reduced eNOS phosphorylation likely through G12/13-mediated RhoA pathway and inhibited eNOS expression via Gi-mediated inhibition of cAMP/PKA/KLF4 pathway in cultured GECs. In vivo, knockout of GPR56 attenuated albuminuria and glomerular injury and restored expression of eNOS and KLF4 in GECs in mice with DKD.
Conclusion
Taken together, these findings suggest a critical role of GPR56 and its underlined mechanism in regulation of GEC injury in early DKD.
Funding
- NIDDK Support