Abstract
NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2.
Highlights
NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress
Through the analysis of NEKO mice, we found a novel phenotype in the kidney, which is attributed to the full activation of Nrf[2] by complete deletion of Keap[1]
Nqo[1] and Gclc, prototypical Nrf[2] target genes[2], were upregulated in most tissues of Keap[1] À / À ::Nrf2Flox/Flox mice, whereas Nqo[1] and Gclc induction was reduced in the oesophagus and skin but not in the other tissues in NEKO mice (Fig. 1a and Supplementary Fig. 1)
Summary
NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. We show that deletion of oesophageal Nrf[2] in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Knockdown of the Keap[1] gene due to floxation of the Keap[1] locus with loxP sites leads to the constitutive accumulation of Nrf[2] throughout the body without lethality[9] In this case, Nrf[2] activation is weaker than that of the Keap1-null mice due to the partial retention of Keap[1] expression[9]. Through the analysis of NEKO mice, we found a novel phenotype in the kidney, which is attributed to the full activation of Nrf[2] by complete deletion of Keap[1]
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