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Src inhibition modulates AMBRA1‐mediated mitophagy to counteract endothelial‐to‐mesenchymal transition in renal allograft fibrosis.

Authors :
Gui, Zeping
Liu, Xuzhong
Xu, Zhen
Feng, Dengyuan
Hang, Zhou
Zheng, Ming
Chen, Hao
Fei, Shuang
Sun, Li
Tao, Jun
Han, Zhijian
Ju, Xiaobin
Gu, Min
Tan, Ruoyun
Wang, Zijie
Source :
Cell Proliferation. Jun2024, p1. 20p. 9 Illustrations.
Publication Year :
2024

Abstract

Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial‐to‐mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single‐cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1‐mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin‐6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin‐mediated mitophagy. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
09607722
Database :
Academic Search Index
Journal :
Cell Proliferation
Publication Type :
Academic Journal
Accession number :
178114178
Full Text :
https://doi.org/10.1111/cpr.13699