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Glucocorticoid-transactivated TSC22D3 attenuates hypoxia- and diabetes-induced Muller glial galectin-1 expression via HIF-1 alpha destabilization
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| Title: | Glucocorticoid-transactivated TSC22D3 attenuates hypoxia- and diabetes-induced Muller glial galectin-1 expression via HIF-1 alpha destabilization |
| Authors: | Kanda, Atsuhiro Browse this author →KAKEN DB | | Hirose, Ikuyo Browse this author | | Noda, Kousuke Browse this author →KAKEN DB | | Murata, Miyuki Browse this author →KAKEN DB | | Ishida, Susumu Browse this author →KAKEN DB |
| Keywords: | diabetic retinopathy | | galectin-1 | | glucocorticoid | | HIF-1 alpha | | hypoxia | | Muller glia | | transactivation |
| Issue Date: | Apr-2020 |
| Publisher: | John Wiley & Sons |
| Journal Title: | Journal of cellular and molecular medicine |
| Volume: | 24 |
| Issue: | 8 |
| Start Page: | 4589 |
| End Page: | 4599 |
| Publisher DOI: | 10.1111/jcmm.15116 |
| Abstract: | Galectin-1/LGALS1, a newly recognized angiogenic factor, contributes to the pathogenesis of diabetic retinopathy (DR). Recently, we demonstrated that glucocorticoids suppressed an interleukin-1 beta-driven inflammatory pathway for galectin-1 expression in vitro and in vivo. Here, we show glucocorticoid-mediated inhibitory mechanism against hypoxia-inducible factor (HIF)-1 alpha-involved galectin-1 expression in human Muller glial cells and the retina of diabetic mice. Hypoxia-induced increases in galectin-1/LGALS1 expression and promoter activity were attenuated by dexamethasone and triamcinolone acetonide in vitro. Glucocorticoid application to hypoxia-stimulated cells decreased HIF-1 alpha protein, but not mRNA, together with its DNA-binding activity, while transactivating TSC22 domain family member (TSC22D)3 mRNA and protein expression. Co-immunoprecipitation revealed that glucocorticoid-transactivated TSC22D3 interacted with HIF-1 alpha, leading to degradation of hypoxia-stabilized HIF-1 alpha via the ubiquitin-proteasome pathway. Silencing TSC22D3 reversed glucocorticoid-mediated ubiquitination of HIF-1 alpha and subsequent down-regulation of HIF-1 alpha and galectin-1/LGALS1 levels. Glucocorticoid treatment to mice significantly alleviated diabetes-induced retinal HIF-1 alpha and galectin-1/Lgals1 levels, while increasing TSC22D3 expression. Fibrovascular tissues from patients with proliferative DR demonstrated co-localization of galectin-1 and HIF-1 alpha in glial cells partially positive for TSC22D3. These results indicate that glucocorticoid-transactivated TSC22D3 attenuates hypoxia- and diabetes-induced retinal glial galectin-1/LGALS1 expression via HIF-1 alpha destabilization, highlighting therapeutic implications for DR in the era of anti-vascular endothelial growth factor treatment. |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/78420 |
| Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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