title: Novel effect of the inhibitor of mitochondrial cyclophilin D activation, N-methyl-4-isoleucine cyclosporin, on renal calcium crystallization.
abstract: OBJECTIVE
  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, 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.
  
  
  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.
authors.affiliation: Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Niimi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasui
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okada
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Hirose
authors.forename: Yasue
authors.initials: Y
authors.lastname: Kubota
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Umemoto
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kawai
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tozawa
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kohri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002129:Calcium Oxalate / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006959:Hyperoxaluria / Q000188:drug therapy* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D002129:Calcium Oxalate; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D021983:Cyclophilins
keywords: N-methyl-4-isoleucine cyclosporin; cyclophilin D; oxidative stress; renal calcium crystallization; renal tubular cell injury