Besides the effect on high blood pressure, T-type calcium channel blocker has been reported to exert a renoprotective effect in experimental models with renal fibrosis. However, the exact mechanism of T-type calcium channel blocker on tubulointerstitial fibrosis has not been fully elucidated. In the present study, we investigated whether the renoprotective effect of T-type calcium channel blocker is associated with modulation of the signaling of oxidative stress-induced renal fibrosis.Design and Method:
Treatment with a nonhypotensive dose of efonidipine, a T-type calcium channel blocker, or nifedipine, an L-type channel blocker, was initiated one day before unilateral ureteral obstruction (UUO) in C57BL6/J mice, and was continued until 3 and 7 days after UUO. Markers of renal fibrosis and oxidative stress were evaluated.Results:
In the obstructed kidneys of UUO mice, treatment with efonidipine significantly attenuated interstitial fibrosis, collagen deposition and inflammation increased by UUO creation compared with treatment with nifedipine. Additionally, efonidipine significantly increased the expression of antioxidant enzymes such as HO-1, NQO1, catalase and SOD1. Increased apoptotic cell death and decreased Bcl-2 expression in the obstructed kidneys were also significantly ameliorated by treatment with efonidipine. Furthermore, the expression of the histone acetyltransferase p300/CBP-associated factor, which is known as a regulator of inflammatory molecules, was significantly inhibited by efonidipine. These beneficial effects of efonipidine were attributed to the increased nuclear expression of nuclear factor-erythroid-2-related factor 2 (Nrf2) on UUO day 3 and the increased expressions of both total and nuclear Nrf2 with elevated Kelch-like ECH-associated protein 1 on UUO day 7, suggesting that efonidipine would promote activation of Nrf2 differently depending time course after UUO. By contrast, nifedipine had little effect on antioxidant enzymes, anti-apoptotic protein and Nrf2 signaling.Conclusions:
These results suggest that T-type calcium channel blocker exerts beneficial effects in renal interstitial fibrosis by activating Nrf2 and subsequent antioxidant enzymes.