Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus

Takafumi Suzuki (), Shiori Seki, Keiichiro Hiramoto, Eriko Naganuma, Eri H. Kobayashi, Ayaka Yamaoka, Liam Baird, Nobuyuki Takahashi, Hiroshi Sato and Masayuki Yamamoto ()
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Takafumi Suzuki: Tohoku University Graduate School of Medicine
Shiori Seki: Tohoku University Graduate School of Medicine
Keiichiro Hiramoto: Tohoku University Graduate School of Medicine
Eriko Naganuma: Tohoku University Graduate School of Medicine
Eri H. Kobayashi: Tohoku University Graduate School of Medicine
Ayaka Yamaoka: Tohoku University Graduate School of Medicine
Liam Baird: Tohoku University Graduate School of Medicine
Nobuyuki Takahashi: Tohoku University Graduate School of Pharmaceutical Sciences
Hiroshi Sato: Tohoku University Graduate School of Pharmaceutical Sciences
Masayuki Yamamoto: Tohoku University Graduate School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14577

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