Abstract: FR-PO1043
Activation of GPER1 in macrophage ameliorates Unilateral Ureteral Obstruction (UUO)-Induced Renal Fibrosis
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Gu, Xiangchen, Shanghai University of Traditional Chinese Medicine Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai, China
- Xie, Lin, Shanghai University of Traditional Chinese Medicine Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai, China
- Cheng, Ye, Shanghai University of Traditional Chinese Medicine Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai, Shanghai, China
- Wang, Yi, Shanghai University of Traditional Chinese Medicine Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai, Shanghai, China
- Chen, Min, Shanghai University of Traditional Chinese Medicine Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai, Shanghai, China
Background
Numerous studies have established the fundamental role of macrophages in the process of renal fibrosis. Interestingly, emerging data suggested that G protein-coupled estrogen receptor 1 (GPER1), a novel estrogen receptor, plays a ubiquitous role in regulating macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis remains unknown.
Methods
First, we pretreated ovariectomized (OVX) female and male mice with G-1 (GPER1 agonist) and subjected them to UUO (Ureteral Unilateral Obstruction) surgeries. And renal fibrosis and M1 and M2 macrophage infiltration were analyzed. Next, using CRISPR/Cas9 gene editing technique, we also generated global knockout Gper1 mice. We performed UUO modeling on the male Gper1-/- mice and measured the degree of renal fibrosis and inflammation. In in vitro study, bone marrow-derived macrophages were treated with G-1 in response to LPS/Interferon γ or Interleukin 4 and cocultured with PTECs (primary tubular epithelial cells) or fibroblasts.
Results
Compared to vehicle-treated OVX female and male mice subjected to UUO, both G-1-treated OVX female and male UUO mice exhibited fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues, respectively. On the other hand, Gper1 deletion accelerated renal fibrosis and enhanced chemokines and proinflammatory cytokines expression. In vitro study demonstrated that GPER1 activation prevented M0 macrophages from polarizing towards the M1 and M2 phenotypes. The Gene Ontology analysis of differentially expressed genes in macrophages treated with or without G-1 indicated that GPER1 activation was primarily involved in the inactivation of MAPK pathways, which was further validated by immunoblotting. In addition, PTECs cocultured with G1-pretreated M1 macrophages exhibited fewer injuries and immune activation, and fibroblasts cocultured with G1-pretreated M2 macrophages showed downregulated extracellular matrix expression.
Conclusion
Overall, our study is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage polarization. These results indicate that GPER1 may serve as a promising therapeutic target for the treatment of renal fibrosis.
Funding
- Government Support – Non-U.S.