Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus

Nat Commun. 2017 Feb 24:8:14577. doi: 10.1038/ncomms14577.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 2 / metabolism
  • Cell Differentiation / genetics
  • Diabetes Insipidus, Nephrogenic / genetics
  • Diabetes Insipidus, Nephrogenic / pathology*
  • Disease Models, Animal
  • Female
  • Humans
  • Hydronephrosis / genetics
  • Hydronephrosis / pathology*
  • Kelch-Like ECH-Associated Protein 1 / genetics*
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / genetics
  • Polyuria / genetics
  • Polyuria / pathology*
  • Renal Reabsorption / genetics

Substances

  • Aqp2 protein, mouse
  • Aquaporin 2
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse