title: T-type calcium channel blocker attenuates unilateral ureteral obstruction-induced renal interstitial fibrosis by activating the Nrf2 antioxidant pathway.
abstract: Besides its effect on high blood pressure, T-type calcium channel blocker is renoprotective in experimental models of renal fibrosis. However, the exact mechanism of T-type calcium channel blocker on tubulointerstitial fibrosis is unclear. 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. Treatment with a non-hypotensive 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. In the obstructed kidneys, 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 the antioxidant enzymes heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, catalase and superoxide dismutase 1. Increased apoptotic cell death and decreased B-cell lymphoma 2 expression were also significantly ameliorated by efonidipine. The expression of the histone acetyltransferase p300/CBP-associated factor, 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. The data indicate that T-type calcium channel blocker exerts beneficial effects in renal interstitial fibrosis by activating Nrf2 and subsequent antioxidant enzymes.
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Soojeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Minyoung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Koh
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Ho-Shik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Shin
keywords: Calcium channel blocker; antioxidant; nuclear factor-erythroid-2-related factor 2; oxidative stress; renal fibrosis