During potassium (K) depletion, many adaptive responses are likely mediated through a complex network that involves expression of a variety of genes. We identified that the Nrf2 gene was differentially expressed between normal and K-depleted rat kidney.To investigate the effect of Nrf2 on colonic H/K-ATPase and kNBC1, overexpression of Nrf2 was carried out in 293T and CV1 cell lines, and experiments were conducted in low-K media. Sp family was cotransfected with Nrf2 to examine the relationship between the 2 molecules and their effect on ion transporters.Ion transporters were activated by overexpression of Nrf2 and cotransfection of Nrf2 with Sp family genes showed additional enhancement of colonic H/K-ATPase and kNBC1 expression and their promoter activities. Pretreatment with low-K media increased the transcriptional activity of Nrf2, colonic H/K-ATPase and kNBC1. Furthermore, transfection of dominant-negative Nrf2 completely abolished low-K-mediated expression of the ion transporters.These results suggest that Nrf2 mediates transcriptional activation of colonic H/K-ATPase and kNBC1 in response to K-depleted stress and augments Sp family-mediated expression of these ion transporters.