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The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis

Authors :
Weiwei Liu
Yang Yi
Chuanfu Zhang
Baojuan Zhou
Lin Liao
Wenrui Liu
Jing Hu
Qiming Xu
Jie Chen
Jianrao Lu
Source :
Frontiers in Cell and Developmental Biology, Vol 8 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.

Details

Language :
English
ISSN :
2296634X
Volume :
8
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cell and Developmental Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.2080d928dce244028073c3fc37fc77d1
Document Type :
article
Full Text :
https://doi.org/10.3389/fcell.2020.616747