Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria.
Robust neuroprotective effects have been shown for minocycline. Whether it also protects nonneuronal cells or tissues is unknown. More importantly, the mechanisms of minocycline protection appear multifaceted and remain to be clarified. Here we show that minocycline can protect kidney epithelial cells in vitro and protect the kidneys from ischemic injury in vivo. We further show that Bcl-2 is a key molecular determinant of minocycline protection. Minocycline protected kidney epithelial cells against apoptosis induced by hypoxia, azide, cisplatin, and staurosporine. The protection occurred at mitochondria, involving the suppression of Bax accumulation, outer membrane damage, and cytochrome c release. Minocycline induced Bcl-2, which accumulated in mitochondria and interacted with death-promoting molecules including Bax, Bak, and Bid. Down-regulation of Bcl-2 by specific antisense oligonucleotides abolished the cytoprotective effects of minocycline. Thus, minocycline can protect neuronal as well as nonneuronal cells and tissues. One mechanism for minocycline protection involves the induction of Bcl-2, an antiapoptotic protein.
Wang
Jinzhao
J
Department of Cell Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912, USA.
Wei
Qingqing
Q
Wang
Cong-Yi
CY
Hill
William D
WD
Hess
David C
DC
Dong
Zheng
Z
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D000860:Hypoxia; D020287:In Situ Nick-End Labeling; D007511:Ischemia; D007668:Kidney / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008911:Minocycline / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019810:Sodium Azide / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
D000900:Anti-Bacterial Agents; C494774:Bak1 protein, rat; C494828:Bax protein, rat; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019810:Sodium Azide; D020169:Caspases; D008911:Minocycline; D019311:Staurosporine; D002945:Cisplatin