Abstract: SA-PO822
The Histone Demethylase Jumonji Domain-Containing Protein 3 Acts as an Epigenetic Suppressor of Renal Fibrosis
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Xiong, Chongxiang, Rhode Island Hospital, Providence, Rhode Island, United States
- Zou, Hequn, The 3rd Affiliated Hospital of Southern Medical University, Guangzhou, China
- Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background
The histone demethylase Jumonji domain-containing protein 3 (JMJD3) is the enzyme that induces demethylation of histone H3 lysine 27 (H3K27) and its activation is involved in the tumor genesis. Although activation of H3K27 methyltransferase has been shown to be required for renal interstitial fibroblast activation and renal fibrogenesis, the role of JMJD3 in these processes remains elusive.
Methods
In this study, we examined the effect of pharmacological inhibition of JMJD3 on renal fibroblast activation and renal fibrosis development in a murine model of unilateral ureteral obstruction.
Results
Following unilateral ureteral obstruction, expression levels of JMJD3 and methylated H3K27 were increased in the kidney. Administration of GSKJ4, a specific inhibitor of JMJD3, aggravated renal fibrosis and increased expression of alpha-smooth muscle actin (alpha-SMA), a hallmark of myofibroblasts (active fibroblasts) and promoted deposition of collagen I, one of major extracellular matrix proteins. GSKJ4 inhibition also increased expression of transforming growth factor β1 (TGF-b1) and enhanced the phosphorylation of Smad3, a key molecule of TGF-β signaling. Moreover, GSKJ4 potentiated expression of Notch1 and Notch3 as well as phosphorylation of NF-κB and Stat3. Finally, treatment with GSKJ4 increased expression of alpha-SMA , collagen I and fibronectin in cultured renal epithelial cells.
Conclusion
Collectively, these data suggest that JMJD3 functions as a suppressor of renal fibroblasts and renal fibrosis in the kidney after ureteral obstruction.
Funding
- NIDDK Support