Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway.
Adult
Allografts
/ immunology
Animals
Autophagosomes
/ immunology
Autophagy
/ genetics
Autophagy-Related Proteins
/ genetics
Cell Line
Datasets as Topic
Disease Models, Animal
Down-Regulation
/ immunology
Endothelial Cells
/ pathology
Epithelial-Mesenchymal Transition
/ immunology
Female
Fibrosis
Gene Knockdown Techniques
Graft Rejection
/ immunology
Humans
Kidney
/ immunology
Kidney Transplantation
/ adverse effects
Male
NF-kappa B
/ metabolism
Proteolysis
Rats
Signal Transduction
/ immunology
Vesicular Transport Proteins
/ metabolism
ATG16L
EndMT
autophagy
chronic renal graft dysfunction
inflammatory cytokines
renal interstitial fibrosis
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
07
01
2021
accepted:
15
03
2021
entrez:
30
4
2021
pubmed:
1
5
2021
medline:
28
9
2021
Statut:
epublish
Résumé
Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs).
Identifiants
pubmed: 33927720
doi: 10.3389/fimmu.2021.650424
pmc: PMC8076642
doi:
Substances chimiques
ATG16L1 protein, human
0
Autophagy-Related Proteins
0
NF-kappa B
0
Vesicular Transport Proteins
0
Atg16L1 protein, rat
EC 3.6.1.-
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
650424Informations de copyright
Copyright © 2021 Gui, Suo, Wang, Zheng, Fei, Chen, Sun, Han, Tao, Ju, Yang, Gu and Tan.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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