Abstract: FR-OR106
DOT1L Inhibition Attenuates Renal Fibrosis through Suppressing Multiple Profibrotic Signaling Pathways and Preserving Expression of Smad7 and Klotho
Session Information
- Signaling in CKD Progression
October 26, 2018 | Location: 23A, San Diego Convention Center
Abstract Time: 05:18 PM - 05:30 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Liu, Lirong, Rhode Island Hospital, Providence, Rhode Island, United States
- Zhou, Xiaoxu, Rhode Island Hospital, Brown University, Providence, Rhode Island, United States
- Xiong, Chongxiang, Rhode Island Hospital, Providence, Rhode Island, United States
- Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background
Disruptor of telomeric silencing-1 like (DOT1L) protein specifically catalyzes the methylation of histone H3 on lysine-79 and is implicated in leukemia and some solid tumors, but its role in tissue fibrosis remains unknown.
Methods
In this study, we examined the role of DOT1L in renal fibroblast activation, epithelial-mesenchymal transition and renal fibrosis development in vitro and in vivo.
Results
We demonstrated that injury to the kidney increased DOT1L expression and H3K79 dimethylation (H3K79me2) in renal tubules and myofibroblasts in a murine model of unilateral ureteral obstruction. Administration of EZP5676, a highly selective inhibitor of DOT1L, attenuated renal fibrosis as evidenced by decreased activation of renal interstitial fibroblasts and reduced deposition of extracellular components. Treatment with EZP5676 or DOT1L siRNA also inhibited transforming growth factor β1 and serum -induced activation of renal interstitial fibroblasts and epithelial-mesenchymal transition (EMT) in vitro. Moreover, blocking DOT1L abrogated injury-induced epithelial G2/M arrest; reduced expression of Snail and Twist, two transcription factors that drive EMT; downregulated Notch1, a transmembrane receptor protein associated with renal fibrosis; and inactivated several profibrotic signaling molecules, including Smad3, epidermal growth factor receptor, platelet growth factor receptor, STAT3, AKT as well as NF-κB in the injured kidney. Conversely, DOT1L inhibition increased expression of phosphatase and tensin homolog, a protein associated with dephosphorylation of tyrosine kinase receptors, and prevented decline in levels of klotho and Smad7, two renoprotective factors.
Conclusion
Our data indicate that targeting DOT1L inhibits activation of renal fibroblasts, EMT and renal fibrosis by suppressing activation of multiple profibrotic signaling pathways and retaining expression of renoprotective factors. DOT1L could be a novel therapeutic target for treatment of fibrotic renal diseases.
Funding
- NIDDK Support