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NRF2 Is Required for Neonatal Beta-Cell Growth by Maintaining Redox Balance and Promoting Mitochondrial Biogenesis and Function

ABSTRACT: Due to the limited expression of several antioxidant enzymes, β-cells are highly vulnerable to high ROS levels, which can lead to the reduction of functional β-cell mass. During early postnatal ages, both human and rodent β-cells go through a burst of proliferation that quickly declines with age. Here we discovered that the expression of the master antioxidant regulator, Nrf2, is increased during this postnatal burst of β-cell proliferation in humans. Additionally, data from β-cell specific Nrf2 deletion in mice demonstrated that Nrf2 is required for β-cell proliferation, β-cell survival, β-cell identity and β-cell mass expansion at early stages of life. Daily administration of antioxidant NAC to newborn mice showed that Nrf2 mechanism of action strongly relies on maintaining normal redox balance. Interestingly, RNAseq of islets isolated from β-cell specific Nrf2 deleted mice suggests that Nrf2 regulates neonatal β-cell proliferation by promoting mitochondrial ATP synthesis. Our study highlights Nrf2 as an essential transcription factor for maintaining redox balance as well as mitochondrial biogenesis and function to support neonatal β-cell growth and for maintaining functional β-cell mass in adulthood under metabolic stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE242718 | GEO | 2023/12/19

REPOSITORIES: GEO

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Project description:Background: Nrf2 is an essential cytoprotective transcription factor. However, association of Nrf2 in organ development and neonatal disease is rarely examined. Hyperoxia exposure to newborn rodents generates pulmonary phenotypes which resemble bronchopulmonary dysplasia (BPD) of prematurity. Methods: To investigate the role of Nrf2 in lung maturation and BPD pathogenesis, Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) neonates were exposed to air or hyperoxia (O2). Transcriptome analysis determined Nrf2-directed mechanisms in premature lung. Lung injury was assessed by bronchoalveolar lavage analysis and histopathology. Results: In Nrf2-/- neonates, basal expression of cell cycle machinery, redox balance, and lipid/carbohydrate metabolism genes were suppressed while immunity genes were overexpressed compared to Nrf2+/+ pups. O2-induced mortality and pulmonary inflammation/injury were significantly higher in Nrf2-/- than in Nrf2+/+. Lung DNA lesion and oxidation were greater in Nrf2-/- than in Nrf2+/+, constitutively and after O2. Nrf2-dependent genes modulated cellular growth/proliferation, defense, immunity, and lipid metabolism against hyperoxia. Bioinformatic elucidation of Nrf2 binding motifs and augmented O2-induced inflammation in genetically deficient neonates validated Gpx2 and Marco as Nrf2 effectors. Conclusion: Overall, Nrf2 in underdeveloped lungs orchestrated cell cycle, morphogenesis, and immunity as well as cellular defense constitutively and under oxidant stress. Results provide putative molecular mechanisms of Nrf2-directed lung alveolarization and BPD of prematurity. PARALLEL study design with 42 samples comparing 14 groups of age (P1 to P4 corresponding to day 0 to day 3 animals), gene, and exposure: (4 groups Nrf+/+ wild type P1-P4 air exposure) (4 groups Nrf -/- knockout P1-P4 air exposure), (3 groups Nrf+/+ wild type P2-P4 with 100 percent O2 (hyperoxia exposure) and 3 groupsNrf -/- knockout P2-P4 with 100 percent O2 (hyperoxia exposure)) Biological replicates: 3 per group

Project description:Background: NRF2 is an essential cytoprotective transcription factor inducing antioxidant response element (ARE)-bearing genes. However, association of NRF2 with lung development has not been examined. Human lungs are not fully developed until 2-3 years of and they are fully matured at about 8 years. Murine lungs at birth are immature (at saccular stage of lung development) and have been used to study developmental lung disorders. Methods: To investigate (1) the transcriptome changes during lung development and (2) the role of NRF2 in lung development and maturation in mice, lungs were harvested from Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) mouse embryos, neonates and adults. Microarray and pathway analysis determined NRF2-directed mechanisms underlying lung development and maturation. Results: Nrf2 mRNA expression was peack at embryonic days E17.5-E18.5 (immediately before birth) probably to increase antioxidant apparatus to prepare against high O2 environment after birth. The pseudoglandular phase lungs (E13-E15) are undergoing vigorous cell proliferation under the control of high-fidelity DNA damage repair system. Fetal lungs (E13.5-E17.5) are lack in immune system, xenobiotic metabolism, and tissue damage genes. After birth at postnatal day 1 (PND1), lung cell division is quiescent but transporters and lipid metabolism are activated. When lung enters alveolar phase (PND4), cell proliferation is resumed. Mature lungs (PND14-P42) have heightened networks of host defense systems (immunity, antioxidants) and cellular injury and abnormality (e.g., glucose metabolism disorder). Nrf2 deletion in fetal lung (E13.5-E17.5) altered developmental, immunity, and metabolism genes, and it may have affected lung branching. Nrf2 deletion affected lung transcriptome changes the most at E17.5 when Nrf2 message level is maximum (E17.5-E18.5). Nrf2 deletion in newborn lung (PND0) decreased cell cycle progress and DNA damage repair. Nrf2 deletion in neonatal lung (PND1-4) enhanced tissue injury/cell death and inhibited developmental cell differentiation. Nrf2 deletion in matured mouse lung (PND42) affected not only antioxidant pathway but also immune responses and connective tissue cell migrations. Conclusion: Overall, NRF2 plays multiple roles in underdeveloped lungs and associated with lung morphogenesis, immunity, cell cycle progress, tissue differentiation and metabolism as well as cellular defense. Results provide putative molecular mechanisms of NRF2-directed lung morphogenesis and maturation.

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NRF2 Is Required for Neonatal Beta-Cell Growth by Maintaining Redox Balance and Promoting Mitochondrial Biogenesis and Function

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