Mitochondrial permeability transition pore opening induces the initial process of renal calcium crystallization

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• 作者：Kazuhiro Niimi^a ; Takahiro Yasui^a ; ^{yasui@med.nagoya-cu.ac.jp} ; Masahito Hirose^b ; Shuzo Hamamoto^a ; Yasunori Itoh^c ; Atsushi Okada^a ; Yasue Kubota^a ; Yoshiyuki Kojima^a ; Keiichi Tozawa^a ; Shoichi Sasaki^a ; Yutaro Hayashi^a ; Kenjiro Kohri^a
• 关键词：COM ; calcium oxalate monohydrate ; CsA ; cyclosporine A ; EG ; ethylene glycol ; 4-HNE ; 4-hydroxy-2-nonenal ; mPTP ; mitochondrial permeability transition pore ; MDA ; malondialdehyde ; 8-OHdG ; 8-hydroxy-2&prime ; -deoxyguanosine ; OPN ; osteopontin ; PLOM ; polarized li
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 April, 2012
• 卷：52
• 期：7
• 页码：1207-1217
• 文件大小：3689 K

摘要

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 渭M). 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.