Abstract: SA-PO330

Protective Effect of DNA Methyltransferase Inhibitor against Progressive Renal Tubulointerstitial Inflammation and Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Koh, Eun Sil, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Soojeong, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Shin, Seok Joon, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Yang, Chul Woo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yong-Soo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Chung, Sungjin, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
Background

Renal fibrosis is the final common pathway of virtually all progressive kidney diseases and correlates with the aggravation of renal function. However, the contributon of DNA methylation to the process of renal fibrosis is not clarified. The current study examined the impact of DNA methyltransferase inhibitor on the progression of inflammation and fibrosis in kidneys of mice with unilateral ureteral obstruction (UUO).

Methods

Zebularine (225 mg/kg/day), a DNA methytrasferase inhibitor, or vehicle was administred to male C57BL/6 mice intraperitoneally for 3 or 7 days after UUO operation.

Results

Administration of zebularine significantly attenuated renal tubulointerstitial fibrosis and inflammation as assessed by trichrome, α-smooth muscle actin, collgen IV, transforming growth factor-β1 staining both at 3 and 7 days after UUO. Zebularine downregulated mRNA expression levels of matric metalloproteinase (MMP) 2, MMP9 and fibronectin, and it also suppressed nuclear factor-κB (NF-κB) and pro-finlammatory cytokines such as tumor necrosis factor-α, interleukin (IL) – 1β and IL-6 in obstructed kidneys. Furthermore, zebularine treatment upregulated the nuclear expression of nuclear factor erythroid-derived 2 like factors 2 (Nrf2) and its subsequent antioxidant downstreams such as heme oxygenase-1, catalase, superoxide dismutase 1 and NAD(P)H: quinone oxidoreduates-1 in UUO kidneys.

Conclusion

Our findings suggest that inhibition of DNA methylation could restore the disrupted balance in pro-inflammatory pathway and antioxidant defence mechanism and alleviate renal fibrosis.