Integrin β8 prevents pericyte-myofibroblast transition and renal fibrosis through inhibiting the TGF-β1/TGFBR1/Smad3 pathway in diabetic kidney disease
Diabetic kidney disease (DKD) is one of the leading causes to develop end-stage kidney disease worldwide. Pericytes are implicated in the development of tissue fibrosis. However, the underlying mechanisms of pericytes in DKD remain largely unknown. We isolated and cultured primary pericytes and rat...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2024
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| In: |
Translational research
Year: 2024, Volume: 265, Pages: 36-50 |
| ISSN: | 1878-1810 |
| DOI: | 10.1016/j.trsl.2023.10.007 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.trsl.2023.10.007 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1931524423001809 
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| Author Notes: | Yiling Cao, Hua Su, Jieyu Zeng, Yaru Xie, Zezhou Liu, Feng Liu, Yang Qiu, Fan Yi, Jihong Lin, Hans-Peter Hammes, Chun Zhang |
| Summary: | Diabetic kidney disease (DKD) is one of the leading causes to develop end-stage kidney disease worldwide. Pericytes are implicated in the development of tissue fibrosis. However, the underlying mechanisms of pericytes in DKD remain largely unknown. We isolated and cultured primary pericytes and rat mesangial cells (HBZY-1). Western blot and qRT-PCR analysis were used to explore the role and regulatory mechanism of Integrin β8/transforming growth factor beta 1 (TGF-β1) pathway. We also constructed pericyte-specific Integrin β8 knock-in mice as the research objects to determine the role of Integrin β8 in vivo. We discovered that reduced Integrin β8 expression was closely associated with pericyte transition in DKD. Overexpressed Integrin β8 in pericytes dramatically suppressed TGF-β1/TGF beta receptor 1 (TGFBR1)/Smad3 signaling pathway and protected glomerular endothelial cells (GECs) in vitro. In vivo, pericyte-specific Integrin β8 knock-in ameliorated pericyte transition, endothelium injury and renal fibrosis in STZ-induced diabetic mice. Mechanistically, Murine double minute 2 (MDM2) was found to increase the degradation of Integrin β8 and caused TGF-β1 release and activation. Knockdown MDM2 could partly reverse the decline of Integrin β8 and suppress pericytes transition. In conclusion, the present findings suggested that upregulated MDM2 expression contributes to the degradation of Integrin β8 and activation of TGF-β1/TGFBR1/Smad3 signaling pathway, which ultimately leads to pericyte transition during DKD progression. These results indicate MDM2/Integrin β8 might be considered as therapeutic targets for DKD. |
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| Item Description: | Online verfügbar: 4 November 2023 Gesehen am 29.07.2024 |
| Physical Description: | Online Resource |
| ISSN: | 1878-1810 |
| DOI: | 10.1016/j.trsl.2023.10.007 |