Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis
| Autor: | Bohui Yin, Huihui Cao, Fenfen Peng, Xiaoyang He, Shuting Li, Jiangping Xu, Xiaowen Chen, Congwei Luo, Haibo Long, Wangqiu Gong, Jing Xiao, Yanxia Liu, Yiqun Zeng |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Senescence
Male Small interfering RNA autophagy Brahma-related gene 1 Cell Cycle Proteins Molecular Bases of Health & Disease Renal fibrosis Gene silencing cellular senescence Animals Humans Wnt Signaling Pathway Research Articles Wnt/β-catenin Chemistry urogenital system Pharmacology & Toxicology Autophagy Wnt signaling pathway DNA Helicases Nuclear Proteins Epithelial Cells General Medicine Fibroblasts Gastrointestinal Renal & Hepatic Systems renal fibrosis Fibrosis Signaling Cell biology Rats Mice Inbred C57BL Disease Models Animal HEK293 Cells Kidney Tubules Catenin Cytokines Ectopic expression Kidney Diseases Transcription Factors Ureteral Obstruction |
| Zdroj: | Clinical Science (London, England : 1979) |
| ISSN: | 1470-8736 0143-5221 |
| Popis: | Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis. |
| Databáze: | OpenAIRE |
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