The Protective Effect of Zebularine, an Inhibitor of DNA Methyltransferase, on Renal Tubulointerstitial Inflammation and Fibrosis

by Selleckchem | May 22 2023

Renal fibrosis, the final pathway of chronic kidney disease, is caused by genetic and epigenetic mechanisms. Although DNA methylation has drawn attention as a developing mechanism of renal fibrosis, its contribution to renal fibrosis has not been clarified. To address this issue, the effect of zebularine, a DNA methyltransferase inhibitor, on renal inflammation and fibrosis in the murine unilateral ureteral obstruction (UUO) model was analyzed. Zebularine significantly attenuated renal tubulointerstitial fibrosis and inflammation. Zebularine decreased trichrome, α-smooth muscle actin, collagen IV, and transforming growth factor-β1 staining by 56.2%. 21.3%, 30.3%, and 29.9%, respectively, at 3 days, and by 54.6%, 41.9%, 45.9%, and 61.7%, respectively, at 7 days after UUO. Zebularine downregulated mRNA expression levels of matrix metalloproteinase (MMP)-2, MMP-9, fibronectin, and Snail1 by 48.6%. 71.4%, 31.8%, and 42.4%, respectively, at 7 days after UUO. Zebularine also suppressed the activation of nuclear factor-κB (NF-κB) and the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, by 69.8%, 74.9%, and 69.6%, respectively, in obstructed kidneys. Furthermore, inhibiting DNA methyltransferase buttressed the nuclear expression of nuclear factor (erythroid-derived 2)-like factor 2, which upregulated downstream effectors such as catalase (1.838-fold increase at 7 days, p < 0.01), superoxide dismutase 1 (1.494-fold increase at 7 days, p < 0.05), and NAD(P)H: quinone oxidoreduate-1 (1.376-fold increase at 7 days, p < 0.05) in obstructed kidneys. Collectively, these findings suggest that inhibiting DNA methylation restores the disrupted balance between pro-inflammatory and anti-inflammatory pathways to alleviate renal inflammation and fibrosis. Therefore, these results highlight the possibility of DNA methyltransferases as therapeutic targets for treating renal inflammation and fibrosis.

Comments：

The above text describes a study that investigated the role of DNA methylation in renal fibrosis, the final pathway of chronic kidney disease. The researchers used a DNA methyltransferase inhibitor called zebularine to investigate its effect on renal inflammation and fibrosis in a murine model of unilateral ureteral obstruction (UUO).

The results showed that zebularine significantly attenuated renal tubulointerstitial fibrosis and inflammation. It decreased the expression of various markers of fibrosis and inflammation, including trichrome, α-smooth muscle actin, collagen IV, and transforming growth factor-β1, as well as the mRNA expression levels of matrix metalloproteinase (MMP)-2, MMP-9, fibronectin, and Snail1. Zebularine also suppressed the activation of nuclear factor-κB (NF-κB) and the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in obstructed kidneys.

Furthermore, inhibiting DNA methyltransferase increased the expression of nuclear factor (erythroid-derived 2)-like factor 2, which upregulated downstream effectors such as catalase, superoxide dismutase 1, and NAD(P)H: quinone oxidoreduate-1 in obstructed kidneys. These results suggest that inhibiting DNA methylation can restore the disrupted balance between pro-inflammatory and anti-inflammatory pathways to alleviate renal inflammation and fibrosis.

Overall, these findings highlight the potential of DNA methyltransferases as therapeutic targets for treating renal inflammation and fibrosis.