Abstract: SA-PO814
DNA Methylation Suppresses HoxA5 for Jag1-Notch1 Signaling in Renal Interstitial 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
Author
- Xiao, Xiao, Augusta University, Augusta, United States
Background
DNA methylation has been implicated in the regulation of renal interstitial fibrosis in kidney diseases, but the mechanism remains incompletely understood.
Methods
In this study, we analyzed genome-wide changes in DNA methylation during renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO) by using the reduced representative bisulfite sequencing.
Results
UUO induced renal interstitial fibrosis, which was accompanied by an overall increase in DNA methylation in kidney tissues. 5-aza-2’-deoxycytidine (5-aza, DNA methylation inhibitor) blocked DNA methylation in UUO and suppressed renal fibrosis. Among the genes with altered DNA methylation in UUO, HoxA5 had seven hypermethylated CpG sites on its promoter that were further verified by pyrosequencing. Hypermethylation of HoxA5 was associated with decreased HoxA5 expression in UUO. 5-aza could partially prevent HoxA5 decrease in UUO, further confirming the regulation of HoxA5 by DNA methylation. Overexpression of HoxA5 suppressed renal fibrosis in UUO and attenuated TGF-β-induced fibrotic changes in renal tubular cells. Mechanistically, HoxA5 was shown to repress Jag1 via gene promoter binding, resulting in the suppression of the Jag1-Notch signaling pathway of renal fibrosis.
Conclusion
Together, these results suggest that DNA methylation may promote renal interstitial fibrosis by suppressing HoxA5 for the activation of Jag1-Notch1 signaling.