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Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus

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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
    Tohoku Medical-Megabank Organization)

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.

Suggested Citation

  • Takafumi Suzuki & Shiori Seki & Keiichiro Hiramoto & Eriko Naganuma & Eri H. Kobayashi & Ayaka Yamaoka & Liam Baird & Nobuyuki Takahashi & Hiroshi Sato & Masayuki Yamamoto, 2017. "Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14577
    DOI: 10.1038/ncomms14577
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