NF-E2-related factor-2 (Nrf2) regulates the cellular response to oxidative/electrophilic stresses, and loss of Keap1 increases the Nrf2 protein level. As Keap1-null mice die of esophageal hyperkeratosis, whole-body phenotypes of Nrf2 hyperactivation in adult animals remain to be delineated. Here we show that deleting esophageal Nrf2 in Keap1-null mice the mice survive until adulthood, but develop polyuria with low osmolality and bilateral hydronephrosis. This novel phenotype is to be attributable to defects in water reabsorption caused by a reduction in the level of the aquaporin 2 (AQP2) channel in the kidney. In line, renal tubular deletion of Keap1 generates symptoms of nephrogenic diabetes insipidus, demonstrating that Nrf2 activation in developing tubular cells causes a water reabsorption defect. The rescue of mice from the lethal first hit of Keap1 ablation serves as a useful tool to study novel functions of Nrf2. Overall design: Gene expression in the kidneys of NEKO and control mice. In the organs from NEKO (Keap1–/–::Nrf2Flox/Flox::K5-Cre) mice, except for esophagus, Nrf2 transcription factor is activated due to Keap1-deficiency. Control mice include K1 (Keap1+/–::Nrf2Flox/Flox) and K1Cre (Keap1+/–::Nrf2Flox/Flox::K5-Cre) mice. Samples were obtained from 4 NEKO mice and 4 control mice.