title: Mitochondrial permeability transition pore opening induces the initial process of renal calcium crystallization.
abstract: Renal tubular cell injury induced by oxidative stress via mitochondrial collapse is thought to be the initial process of renal calcium crystallization. Mitochondrial collapse is generally caused by mitochondrial permeability transition pore (mPTP) opening, which can be blocked by cyclosporine A (CsA). Definitive evidence for the involvement of mPTP opening in the initial process of renal calcium crystallization, however, is lacking. In this study, we examined the physiological role of mPTP opening in renal calcium crystallization in vitro and in vivo. In the in vitro study, cultured renal tubular cells were exposed to calcium oxalate monohydrate (COM) crystals and treated with CsA (2 μM). COM crystals induced depolarization of the mitochondrial membrane potential and generated oxidative stress as evaluated by Cu-Zn SOD and 4-HNE. Furthermore, the expression of cytochrome c and cleaved caspase 3 was increased and these effects were prevented by CsA. In the in vivo study, Sprague-Dawley rats were administered 1% ethylene glycol (EG) to generate a rat kidney stone model and then treated with CsA (2.5, 5.0, and 10.0 mg/kg/day) for 14 days. EG administration induced renal calcium crystallization, which was prevented by CsA. Mitochondrial collapse was demonstrated by transmission electron microscopy, and oxidative stress was evaluated by measuring Cu-Zn SOD, MDA, and 8-OHdG generated by EG administration, all of which were prevented by CsA. Collectively, our results provide compelling evidence for a role of mPTP opening and its associated mitochondrial collapse, oxidative stress, and activation of the apoptotic pathway in the initial process of renal calcium crystallization.
authors.affiliation: Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Niimi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasui
authors.forename: Masahito
authors.initials: M
authors.lastname: Hirose
authors.forename: Shuzo
authors.initials: S
authors.lastname: Hamamoto
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Itoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okada
authors.forename: Yasue
authors.initials: Y
authors.lastname: Kubota
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kojima
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tozawa
authors.forename: Shoichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kohri
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism*; D002129:Calcium Oxalate / Q000378:metabolism*; D002478:Cells, Cultured; D003460:Crystallization; D016572:Cyclosporine / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D002129:Calcium Oxalate; D016572:Cyclosporine; D002118:Calcium