Nrf2 regulates curcumin-induced aldose reductase expression indirectly via nuclear factor-kappa B

Abstract

The osmotic response element (ORE) differs from the nuclear factor-kappa B (NF-kappa B) binding sequence by a single base pair; therefore, we investigated the involvement of NF-kappa B 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-kappa B, 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-OREwt gene, but not that of the mutated AR-OREmt, indicating that the ORE is essential for the response to NF-kappa B. The expression of p65, the promoter activity and DNA binding activity of NF-kappa B 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-kappa B in the cellular response of AR to oxidative stress and toxic aldehydes. (C) 2008 Elsevier Ltd. All rights reserved.