Transcription factor Nrf2 regulates promoter activity of mouse aldose reductase (AKR1B3) gene.

Transcription factor Nrf2 regulates gene expression of drug metabolizing enzymes such as glutathione S-transferase via the antioxidant response element, ARE. Aldose reductase (AR), a member of the aldo-keto reductase (AKR) superfamily, metabolizes various endogenous and exogenous aldehydes. The AR gene 5'-flanking region contains a multiple stress response region (MSRR) composed of two putative AREs (ARE1 and ARE2), an AP1 site, and a tonicity response element (TonE). As this region is highly conserved among species, we examined the involvement of Nrf2 in transcriptional regulation of the AR gene. beta-Naphthoflavone, an Nrf2 activator, elevated the level of AR mRNA in HepG2 cells and increased the promoter activity of the mouse AR (AKR1B3) gene. The promoter activity of the AKR1B3 gene, containing MSRR, was also augmented by overexpression of Nrf2. Deletion and mutation analyses indicated that both ARE1 and the AP1 site were essential for the responsiveness to Nrf2, while ARE2 was nonfunctional. The presence of an ARE1 binding protein complex was revealed by electrophoretic mobility shift assay. These findings indicate that Nrf2 regulates the AKR1B3 promoter activity via ARE1 and the AP1 site.