Novel effect of the inhibitor of mitochondrial cyclophilin D activation, N-methyl-4-isoleucine cyclosporin, on renal calcium crystallization

作者：Niimi Kazuhiro; Yasui Takahiro^*; Okada Atsushi; Hirose Yasuhiko; Kubota Yasue; Umemoto Yukihiro; Kawai Noriyasu; Tozawa Keiichi; Kohri Kenjiro

来源：International Journal of Urology, 2014, 21(7): 707-713.

DOI：10.1111/iju.12425

• cyclophilin D
• N-methyl-4-isoleucine cyclosporin
• oxidative stress
• renal calcium crystallization
• renal tubular cell injury

Objectives: To experimentally evaluate the clinical application of N-methyl-4-isoleucine cyclosporin, a novel selective inhibitor of cyclophilin D activation. %26lt;br%26gt;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, Sprague-Dawley 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 Pizzolato 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. %26lt;br%26gt;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. %26lt;br%26gt;Conclusions: Herein we first report a new treatment agent determining renal calcium crystallization through cyclophilin D activation.

• 出版日期2014-7