MP34-05 N-METHYL-4-ISOLEUCINE CYCLOSPORINE, AN INHIBITOR OF MITOCHONDRIAL CYCLOPHILIN D ACTIVATION, PREVENTS KIDNEY STONE FORMATION BY ALLEVIATING OXIDATIVE STRESS IN RENAL TUBULAR CELLS

You have accessJournal of UrologyStone Disease: Basic Research II1 Apr 2015MP34-05 N-METHYL-4-ISOLEUCINE CYCLOSPORINE, AN INHIBITOR OF MITOCHONDRIAL CYCLOPHILIN D ACTIVATION, PREVENTS KIDNEY STONE FORMATION BY ALLEVIATING OXIDATIVE STRESS IN RENAL TUBULAR CELLS Takahiro Yasui, Kazuhiro Niimi, Atsushi Okada, Kazumi Taguchi, Yasuhiro Fujii, Yasuhiko Hirose, Yasuhiko Ito, Shuzo Hamamoto, Masahito Hirose, Keiichi Tozawa, Shoichi Sasaki, Yutaro Hayashi, and Kenjiro Kohri Takahiro YasuiTakahiro Yasui More articles by this author , Kazuhiro NiimiKazuhiro Niimi More articles by this author , Atsushi OkadaAtsushi Okada More articles by this author , Kazumi TaguchiKazumi Taguchi More articles by this author , Yasuhiro FujiiYasuhiro Fujii More articles by this author , Yasuhiko HiroseYasuhiko Hirose More articles by this author , Yasuhiko ItoYasuhiko Ito More articles by this author , Shuzo HamamotoShuzo Hamamoto More articles by this author , Masahito HiroseMasahito Hirose More articles by this author , Keiichi TozawaKeiichi Tozawa More articles by this author , Shoichi SasakiShoichi Sasaki More articles by this author , Yutaro HayashiYutaro Hayashi More articles by this author , and Kenjiro KohriKenjiro Kohri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1301AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Oxalate-induced oxidative stress contributes to cell injury and promotes renal deposition of calcium oxalate crystals. Generation of reactive oxygen species (ROS) in mitochondria is closely associated with the pathogenesis of renal tubular cell injury and kidney stone disease. Previously, we demonstrated that mitochondrial permeability transition pore (mPTP) opening by activation of cyclophilin D is associated with mitochondrial collapse, oxidative stress, and activation of the apoptotic pathway in the initial process of renal calcium crystallization. In this study, we evaluated the clinical application of N-methyl-4-isoleucine cyclosporine, a recently reported selective inhibitor of cyclophilin D activation. METHODS Cultured renal tubular cells were exposed to calcium oxalate monohydrate crystals in vitro and then treated with N-methyl-4-isoleucine cyclosporine. To observe changes in the mitochondria, mitochondrial membranes were stained with tetramethylrhodamine ethyl ester perchlorate. For the in vivo studies, Sprague–Dawley rats were assigned to four groups: control group, ethylene glycol group (ethylene glycol was administered to induce renal calcium crystal formation), N-methyl-4-isoleucine cyclosporine group, and ethylene glycol plus N-methyl-4-isoleucine cyclosporine group. Renal calcium crystal formation was detected by Pizzolato staining. Oxidative stress was evaluated by analyzing superoxide dismutase activity and 8-hydroxy-deoxyguanosine levels. Mitochondria in renal tubular cells were observed by transmission electron microscopy, and apoptosis was evaluated by measuring cleaved caspase-3 levels. RESULTS Calcium oxalate monohydrate crystals induced depolarization of the mitochondrial membrane in vitro, and this effect was abrogated by the addition of N-methyl-4-isoleucine cyclosporine. Additionally, in rats, ethylene glycol administration induced renal calcium crystal formation, oxidative stress, mitochondrial collapse, and apoptosis. Treatment with N-methyl-4-isoleucine cyclosporine significantly reduced all of these effects. CONCLUSIONS N-methyl-4-isoleucine cyclosporine may represent a new therapeutic agent for the prevention of kidney stone formation. This is the first report of the use of N-methyl-4-isoleucine cyclosporine as a novel therapeutic agent to prevent renal calcium crystal formation through inhibition of cyclophilin D activation. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e411-e412 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takahiro Yasui More articles by this author Kazuhiro Niimi More articles by this author Atsushi Okada More articles by this author Kazumi Taguchi More articles by this author Yasuhiro Fujii More articles by this author Yasuhiko Hirose More articles by this author Yasuhiko Ito More articles by this author Shuzo Hamamoto More articles by this author Masahito Hirose More articles by this author Keiichi Tozawa More articles by this author Shoichi Sasaki More articles by this author Yutaro Hayashi More articles by this author Kenjiro Kohri More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...