Alpha-tocopherol induces calnexin in renal tubular cells: another protective mechanism against free radical-induced cellular damage.
Pre-administration of alpha-tocopherol is protective against oxidative renal tubular damage and subsequent carcinogenesis by ferric nitrilotriacetate (Fe-NTA) in rats. We searched for mechanisms other than the scavenging effect of alpha-tocopherol with microarray analyses, which implicated calnexin, a chaperone for glycoproteins. Renal mRNA levels of calnexin significantly increased 3h after an injection of Fe-NTA in rats fed a standard diet whereas those fed an alpha-tocopherol-supplemented diet showed an increase prior to injection, but after injection showed a decrease in renal calnexin mRNA levels, with unaltered protein levels. In experiments using LLC-PK1 cells, addition of alpha-tocopherol was protective against oxidative stress by H2O2, concomitant with calnexin induction. Knockdown of calnexin by siRNA significantly reduced this protection. Furthermore, COS-7 cells transfected with the calnexin gene were more resistant to H2O2. Together with the fact that alpha-tocopherol induced N-acetylglucosaminyltransferase 3, our data suggest that alpha-tocopherol modifies glycoprotein metabolism partially by conferring mild ER stress. This adds another molecular mechanism of alpha-tocopherol toward cancer prevention.
Lee
Wen-Hua
WH
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Akatsuka
Shinya
S
Shirase
Tomoyuki
T
Dutta
Khokon Kumar
KK
Jiang
Li
L
Liu
Yu-Ting
YT
Onuki
Janice
J
Yamada
Yoshihiro
Y
Okawa
Katsuya
K
Wada
Youichiro
Y
Watanabe
Akira
A
Kohro
Takahide
T
Noguchi
Noriko
N
Toyokuni
Shinya
S
D000818:Animals; D037281:Calnexin; D002273:Carcinogens / Q000633:toxicity; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000633:toxicity; D005609:Free Radicals / Q000633:toxicity; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D024502:alpha-Tocopherol / Q000008:administration & dosage*
D002273:Carcinogens; D005290:Ferric Compounds; D005609:Free Radicals; D037281:Calnexin; D024502:alpha-Tocopherol; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate