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Novel effect of the inhibitor of mitochondrial cyclophilin D activation, N ‐methyl‐4‐isoleucine cyclosporin, on renal calcium crystallization
Author(s) -
Niimi Kazuhiro,
Yasui Takahiro,
Okada Atsushi,
Hirose Yasuhiko,
Kubota Yasue,
Umemoto Yukihiro,
Kawai Noriyasu,
Tozawa Keiichi,
Kohri Kenjiro
Publication year - 2014
Publication title -
international journal of urology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.172
H-Index - 67
eISSN - 1442-2042
pISSN - 0919-8172
DOI - 10.1111/iju.12425
Subject(s) - pharmacology , chemistry , isoleucine , biochemistry , calcium , medicine , leucine , amino acid
Objectives To experimentally evaluate the clinical application of N ‐methyl‐4‐isoleucine cyclosporin, a novel selective inhibitor of cyclophilin D activation. Methods In vitro, cultured renal tubular cells were exposed to calcium oxalate monohydrate crystals and treated with N ‐methyl‐4‐isoleucine cyclosporin. The mitochondrial membrane was stained with tetramethylrhodamine ethyl ester perchlorate and observed. In vivo , S prague– D awley rats were divided into four groups: a control group, an ethylene glycol group (administration of ethylene glycol to induce renal calcium crystallization), a N ‐methyl‐4‐isoleucine cyclosporin group (administration of N ‐methyl‐4‐isoleucine cyclosporin) and an ethylene glycol + N ‐methyl‐4‐isoleucine cyclosporin group (administration of ethylene glycol and N ‐methyl‐4‐isoleucine cyclosporin). Renal calcium crystallization was evaluated using P izzolato staining. Oxidative stress was evaluated using superoxide dismutase and 8‐hydroxy‐deoxyguanosine. Mitochondria within renal tubular cells were observed by transmission electron microscopy. Cell apoptosis was evaluated using cleaved caspase‐3. Results In vitro , calcium oxalate monohydrate crystals induced depolarization of the mitochondrial membrane potential, which was remarkably prevented by N ‐methyl‐4‐isoleucine cyclosporin. In vivo , ethylene glycol administration induced renal calcium crystallization, oxidative stress, mitochondrial collapse and cell apoptosis in rats, which were significantly prevented by N ‐methyl‐4‐isoleucine cyclosporin. Conclusions Herein we first report a new treatment agent determining renal calcium crystallization through cyclophilin D activation.