Abstract
The Keap1-Nrf2 system serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than one hundred cytoprotective proteins, including antioxidants and phase 2 detoxifying enzymes. Since induction profiles of Nrf2 target genes have been studied exclusively in cultured cells, and not in animal models, their tissue-specificity has not been well characterized. In this paper, we examined and compared the tissue-specific expression of several Nrf2 target genes in zebrafish larvae by whole-mount in situ hybridization (WISH). Seven zebrafish genes (gstp1, mgst3b, prdx1, frrs1c, fthl, gclc and hmox1a) suitable for WISH analysis were selected from candidates for Nrf2 targets identified by microarray analysis. Tissue-restricted induction was observed in the nose, gill, and/or liver for all seven genes in response to Nrf2-activating compounds, diethylmaleate (DEM) and sulforaphane. The Nrf2 gene itself was dominantly expressed in these three tissues, implying that tissue-restricted induction of Nrf2 target genes is defined by tissue-specific expression of Nrf2. Interestingly, the induction of frrs1c and gclc in liver and nose, respectively, was quite low and that of hmox1a was restricted in the liver. These results indicate the existence of gene-specific variations in the tissue specificity, which can be controlled by factors other than Nrf2.
Highlights
Nrf2 is a transcription factor that binds to the antioxidant response element (ARE) and transactivates cytoprotective genes [1,2]
The induction of frrs1c and gclc in liver and nose, respectively, was quite low and that of hmox1a was restricted in the liver. These results indicate the existence of gene-specific variations in the tissue specificity, which can be controlled by factors other than Nrf2
Nrf2 is degraded via the Keap1dependent proteasome pathway, while it is stabilized after cells are exposed to electrophilic or oxidative stress, which transactivates its target genes
Summary
Nrf is a transcription factor that binds to the antioxidant response element (ARE) and transactivates cytoprotective genes [1,2]. We noticed that the expression of gstp, a major target gene for zebrafish Nrf, is not ubiquitous as expected, but is rather restricted in the nose, gill, and liver [8,9,10,11,12,13]. It is unclear whether this tissue-restricted induction is specific for gstp or a common feature for Nrf target genes, since gstp was the only gene available in our study that was suitable for WISH analysis. These results indicate tissuerestricted induction to be a common feature of Nrf target genes, which can be a critical issue for both the pharmacological and clinical applications of Nrf2-activating compounds
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