Abstract: PO2478
Critical Role of Histone Demethylase JMJD3 in the Regulation of Macrophage Polarization and Renal Fibrosis
Session Information
- CKD: Metabolism, Epigenetics, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- An, Changlong, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Jiao, Baihai, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Wang, Yanlin, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background
Chronic kidney disease is characterized by macrophage infiltration and fibrosis. Macrophage infiltration and polarization play an important role in the development of renal fibrosis. However, the mechanisms underlying macrophage polarization and development of renal fibrosis are not fully understood. In this study, we examined the role of histone demethylase JMJD3 in the regulation of macrophage polarization and renal fibrosis.
Methods
To examine the role of JMJD3 in vivo, we generated mice with global or myeloid cell-specific deletion of JMJD3, and we treated wild-type mice with vehicle or GSK-J4, a selective JMJD3 inhibitor. Unilateral ureteral obstruction (UUO) model were used to induce renal fibrosis.
Results
JMJD3 expression was increased in the kidneys during the development of renal fibrosis. Mice with tamoxifen-inducible deletion of JMJD3 (CAG-Cre, floxed JMJD3) or myeloid cell specific deletion of JMJD3 (LysM-Cre, floxed JMJD3) were born normal and had no obvious morphological abnormality in the kidney. Compared with Cre negative, floxed JMJD3 mice, mice with global or myeloid cell-specific deletion of JMJD3 displayed fewer F4/80-positive macrophages, CD206-positive M2 macrophages, and myofibroblasts, and expressed less α-SMA protein in the kidneys following UUO. Furthermore, global or myeloid cell-specific deletion of JMJD3 significantly reduced total collagen deposition and ECM protein production in the kidneys after UUO injury. Real-time RT-PCR showed that global or myeloid cell-specific deletion of JMJD3 attenuated M2 macrophage polarization, fibroblast activation, and extracellular matrix protein production. Moreover, genetic deletion of JMJD3 increased histone Lys 27 dimethylation. Wild-type mice treated with GSK-J4 exhibited fewer M2 macrophages and myofibroblasts and produced less amounts of extracellular matrix proteins in the kidney following UUO.
Conclusion
Our study identifies JMJD3 as a critical regulator of macrophage polarization and development of renal fibrosis. Therefore, JMJD3 may represent a novel therapeutic target for chronic kidney disease.
Funding
- NIDDK Support