Abstract: TH-PO502
Lysine Methyltransferase SMYD2 Inhibition Ameliorates Renal Fibrosis Through Suppression of Renal Fibroblast to Myofibroblast Transition
Session Information
- CKD: Mechanisms - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Liu, Lirong, Guizhou Medical University, Guiyang, GUIZHOU, China
- Liu, Feng, Shanghai East Hospital, Shanghai, China
- Xiong, Chongxiang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
- Tolbert, Evelyn, Rhode Island Hospital, Providence, Rhode Island, United States
- Bayliss, George P., Alpert Medical School, Brown University, Providence, Rhode Island, United States
- Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background
Although SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, has been reported to mediate tumorgenesis and cystic growth, its roles in the pathogenesis of renal fibrosis has not been explored.
Methods
We investigated whether pharmacological inhibition of SMYD2 attenuates renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO). We also used cell culture, immunoblot analysis, staining, and other techniques to study the mechanism by which SMYD2 mediates renal fibrosis and renal fibroblast activation and proliferation.
Results
SMYD2 was upregulated in interstitial fibroblasts and renal tubular epithelial cells of the kidney after urethral obstruction. Targeting inhibition of SMYD2 with AZ505, a highly selective inhibitor of SMYD2, protected mice from activation of renal interstitial fibroblasts and development of renal fibrosis. Mechanistic studies showed that AZ505 treatment reduced obstructive injury –induced arrest of epithelial cells at G2/M phase of cell cycle, phosphorylation of Smad3, ERK1/2, AKT, STAT3 and AKT as well as upregulation of transcriptional factors Snail and Twist. In vitro cultured renal interstitial fibroblasts, treatment with AZ505 or silencing of SMYD2 using specific siRNA also inhibited serum or TGF-b1-induced activation of and proliferation of renal interstitial fibroblasts.
Conclusion
These results implicate that SMYD2 is a key mediator of renal fibroblast activation and renal fibrosis. Given the availability of potent SMYD2 inhibitors, SMYD2 might be a potential therapeutic target for the treatment of chronic fibrotic kidney disease.
Funding
- NIDDK Support