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Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE84780 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA331132

REPOSITORIES: GEO

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Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.

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Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus

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