Smad3 deficiency promotes beta cell proliferation and function in
| Autor: | Jingyi, Sheng, Li, Wang, Patrick Ming-Kuen, Tang, Hong-Lian, Wang, Jian-Chun, Li, Bi-Hua, Xu, Vivian Weiwen, Xue, Rui-Zhi, Tan, Nana, Jin, Ting-Fung, Chan, Xiao-Ru, Huang, Ronald Cw, Ma, Hui-Yao, Lan |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Mice Knockout integumentary system PAX6 Transcription Factor Down-Regulation Type 2 diabetes Diabetes Mellitus Experimental Islet beta cells Pax6 Mice Inbred C57BL Islets of Langerhans Mice Glucose Diabetes Mellitus Type 2 Transforming Growth Factor beta Insulin-Secreting Cells Animals Diabetic Nephropathies Female Smad3 Protein Cell Proliferation Signal Transduction Research Paper Smad3 |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Rationale: Transforming Growth Factor-beta (TGF-β) /Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases, but its role in beta cell function and type 2 diabetes is unknown. Methods: The role of Smad3 in beta cell function under type 2 diabetes condition was investigated by genetically deleting Smad3 from db/db mice. Phenotypic changes of pancreatic islets and beta cell function were compared between Smad3 knockout db/db (Smad3KO-db/db) mice and Smad3 wild-type db/db (Smad3WT-db/db) mice, and other littermate controls. Islet-specific RNA-sequencing was performed to identify Smad3-dependent differentially expressed genes associated with type 2 diabetes. In vitro beta cell proliferation assay and insulin secretion assay were carried out to validate the mechanism by which Smad3 regulates beta cell proliferation and function. Results: The results showed that Smad3 deficiency completely protected against diabetes-associated beta cell loss and dysfunction in db/db mice. By islet-specific RNA-sequencing, we identified 8160 Smad3-dependent differentially expressed genes associated with type 2 diabetes, where Smad3 deficiency markedly prevented the down-regulation of those genes. Mechanistically, Smad3 deficiency preserved the expression of beta cell development mediator Pax6 in islet, thereby enhancing beta cell proliferation and function in db/db mice in vivo and in Min6 cells in vitro. Conclusions: Taken together, we discovered a pathogenic role of Smad3 in beta cell loss and dysfunction via targeting the protective Pax6. Thus, Smad3 may represent as a novel therapeutic target for type 2 diabetes prevention and treatment. |
| Databáze: | OpenAIRE |
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