Knockout of mitochondrial voltage-dependent anion channel type 3 increases reactive oxygen species (ROS) levels and alters renal sodium transport.

Autor: Zou L; From the Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Linck V; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Zhai YJ; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Galarza-Paez L; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Li L; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Yue Q; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Al-Khalili O; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Bao HF; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Ma HP; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Thai TL; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and., Jiao J; From the Department of Nephrology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China, jiaojundong@163.com.; the Institute of Nephrology, Harbin Medical University, Harbin, China., Eaton DC; the Department of Physiology and the Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, and deaton@emory.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2018 Feb 02; Vol. 293 (5), pp. 1666-1675. Date of Electronic Publication: 2017 Nov 27.
DOI: 10.1074/jbc.M117.798645
Abstrakt: It has been suggested that voltage-dependent anion channels (VDACs) control the release of superoxide from mitochondria. We have previously shown that reactive oxygen species (ROS) such as superoxide (O 2 ̇̄ ) and hydrogen peroxide (H 2 O 2 ) stimulate epithelial sodium channels (ENaCs) in sodium-transporting epithelial tissue, including cortical collecting duct (CCD) principal cells. Therefore, we hypothesized that VDACs could regulate ENaC by modulating cytosolic ROS levels. Herein, we find that VDAC3-knockout(KO) mice can maintain normal salt and water balance on low-salt and high-salt diets. However, on a high-salt diet for 2 weeks, VDAC3-KO mice had significantly higher systolic blood pressure than wildtype mice. Consistent with this observation, after a high-salt diet for 2 weeks, ENaC activity in VDAC3-KO mice was significantly higher than wildtype mice. EM analysis disclosed a significant morphological change of mitochondria in the CCD cells of VDAC3-KO mice compared with wildtype mice, which may have been caused by mitochondrial superoxide overload. Of note, compared with wildtype animals, ROS levels in VDAC3-KO animals fed a normal or high-salt diet were consistently and significantly increased in renal tubules. Both the ROS scavenger 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (TEMPOL) and the mitochondrial ROS scavenger (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mito-TEMPO) could reverse the effect of high-salt on ENaC activity and systolic blood pressure in the VDAC3-KO mice. Mito-TEMPO partially correct the morphological changes in VDAC3-KO mice. Our results suggest that knocking out mitochondrial VDAC3 increases ROS, alters renal sodium transport, and leads to hypertension.
(© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze: MEDLINE
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