Nrf2 regulates curcumin-induced aldose reductase expression indirectly via nuclear factor-kappaB.
The osmotic response element (ORE) differs from the nuclear factor-kappaB (NF-kappaB) binding sequence by a single base pair; therefore, we investigated the involvement of NF-kappaB in the induction of aldose reductase (AR) by curcumin. Curcumin, an herb-derived polyphenolic compound, elicited an increase in the expression and promoter activity of the AR gene in a nuclear factor-erythroid 2-related factor 2 (Nrf2)-dependent manner. Small interfering RNA (siRNA) against p65 or BAY11-7082, an inhibitor of NF-kappaB, significantly suppressed the curcumin and/or Nrf2-induced increase in expression levels and promoter activity of the AR gene. BAY11-7082 or siRNA against p65 also attenuated the curcumin-induced increase in the promoter activity of the wild type AR-ORE(wt) gene, but not that of the mutated AR-ORE(mt), indicating that the ORE is essential for the response to NF-kappaB. The expression of p65, the promoter activity and DNA binding activity of NF-kappaB were enhanced in the presence of curcumin in cells that were transfected with Nrf2 compared to those treated with curcumin alone. Cells that had been preincubated with curcumin demonstrated resistance to reactive oxygen species-induced cell damage through the suppressive effects in the generation of reactive aldehydes. These effects were significantly attenuated in the presence of BAY11-7082, indicating the involvement of NF-kappaB in the cellular response of AR to oxidative stress and toxic aldehydes.
Kang
Eun Sil
ES
Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, 92 Chilam-Dong, Jinju 660-751, Republic of Korea.
Kim
Gil Hyeong
GH
Kim
Hyo Jung
HJ
Woo
Im Sun
IS
Ham
Sun Ah
SA
Jin
Hana
H
Kim
Min Young
MY
Kim
Hye Jung
HJ
Lee
Jae Heun
JH
Chang
Ki Churl
KC
Seo
Han Geuk
HG
Hwang
Jin-Yong
JY
D000449:Aldehyde Reductase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D066298:In Vitro Techniques; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology*; D009995:Osmosis; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D013450:Sulfones / Q000494:pharmacology*; D015854:Up-Regulation
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009570:Nitriles; D034741:RNA, Small Interfering; D013450:Sulfones; D000449:Aldehyde Reductase; D003474:Curcumin