Increase of SOX9 promotes hepatic ischemia/reperfusion (IR) injury by activating TGF-β1
- Department of Anesthesiology, China Japan Union Hospital of Jilin University, No.126 Xiantai Street, Changchun, 130033 (China)
- Department of Anesthesiology, The Second Hospital of Jilin University, No.218 Ziqiang Street, Nanguan District, Changchun, 130041 (China)
- Department of Anesthesiology, The First Hospital of Jilin University, No.71, Xinmin Street, Changchun, Changchun, 130021 (China)
Highlights: • Increase in SOX9 expression contributed to IR-associated liver injury. • SOX9 up-regulates TGF-β1 expressions in hepatic tissue of mice after IR injury. • SOX9 promotes hepatic injury by accelerating inflammation and apoptosis in primary hepatocytes through activating TGF-β1. Ischemia/reperfusion (IR) injury causes damage in aerobically metabolizing organs or tissues, which is an essential injury mechanism in various clinical settings. SRY-related high mobility group-Box gene 9 (SOX9) is a transcription factor of the SRY family, modulating various cellular processes, including fibrosis formation and tumor growth. However, the effects of SOX9 on hepatic IR injury have not been explored. In the present study, a hepatic IR injury model was established, supported by a significant histological alteration with high Suzuki scores, and a remarkable up-regulation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Importantly, we found that SOX9 was over-expressed in liver of mice after IR operation. Suppressing SOX9 markedly reduced inflammatory response, as evidenced by the reduced mRNA expressions of tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β and inactivation of inhibitor of κBα (IκBα)/nuclear factor (NF)-κB pathway. In addition, SOX9 suppression alleviated apoptosis in liver of mice after IR injury, as supported by the reduced number of terminal deoxyribonucleotidyl transferse (TdT)-mediated biotin-16-dUTP nick-end labelling (TUNEL)-staining cells and decreased expression of Caspase-3 in liver tissue sections. The role of SOX9 in accelerating hepatic IR injury was further confirmed in primary hepatocytes under hypoxiaand reoxygenation (HR) treatment by enhancing inflammatory response and apoptosis. Of note, we found that transforming growth factor (TGF)-β1 was highly induced in liver of mice after IR injury. HR treatment also stimulated TGF-β1 expressions in vitro. Significantly, SOX9 over-expression-induced inflammation and apoptosis were obviously reduced by pirfenidone (Pirf), TGF-β1 inhibitor. In contrast, TGF-β1 exposure to cells further enhanced inflammation and apoptosis in HR-operated cells either with SOX9 knockdown or over-expression. Therefore, we identified a novel SOX9-dependent pathway that contributed to hepatic IR injury through enhancing inflammation and apoptosis by activating TGF-β1.
- OSTI ID:
- 23105713
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 1; Other Information: Copyright (c) 2018 Published by Elsevier Inc.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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