Gasdermin D is involved in switching from apoptosis to pyroptosis in TLR4-mediated renal tubular epithelial cells injury in diabetic kidney disease.
Animals
Apoptosis
Caspase 1
/ metabolism
Caspase 3
/ metabolism
Caspases
/ metabolism
Diabetes Mellitus
Diabetic Nephropathies
Epithelial Cells
/ metabolism
Interleukin-18
/ metabolism
Intracellular Signaling Peptides and Proteins
/ genetics
Mice
Phosphate-Binding Proteins
/ genetics
Pore Forming Cytotoxic Proteins
/ metabolism
Pyroptosis
RNA, Small Interfering
/ metabolism
Toll-Like Receptor 4
/ genetics
bcl-2-Associated X Protein
/ metabolism
Apoptosis
Diabetic kidney disease
Gasdermin D
Pyroptosis
Toll-like receptor 4
Journal
Archives of biochemistry and biophysics
ISSN: 1096-0384
Titre abrégé: Arch Biochem Biophys
Pays: United States
ID NLM: 0372430
Informations de publication
Date de publication:
30 09 2022
30 09 2022
Historique:
received:
27
02
2022
revised:
01
07
2022
accepted:
01
07
2022
pubmed:
10
7
2022
medline:
27
7
2022
entrez:
9
7
2022
Statut:
ppublish
Résumé
Toll-like receptor 4 (TLR4) mediated pathway plays a pivotal role in promoting tubulointerstitial inflammation and contributes to the progression in type 2 diabetic kidney disease (T2DKD). As the first identified key pyroptosis executor, gasdermin D (GSDMD) is activated by caspases and might be the key protein to switch apoptosis to pyroptosis. It remains unclear that role of TLR4 on canonical pyroptosis pathway, and whether GSDMD is involved in switching from apoptosis to pyroptosis in the TLR4-related tubular injury in T2DKD. Immunohistochemistry staining was used to detect the expression of pyroptosis-related proteins in renal tissues of T2DKD patients. T2DKD models was induced in TLR4 knockout (TLR4 The expression levels of caspase-1, GSDMD, IL-18 and IL-1β were increased in renal biopsy tissues of T2DKD patients and GSDMD expression was positively correlated with tubular injury. Silencing GSDMD attenuated HG-induced IL-18, IL-1β, FN and α-SMA, and reduced pyroptotic cells rate in HK-2 cells. Up-regulation of GSDMD inhibited HG-induced expression of Bax and cleaved caspase-3 and reduced apoptosis rate. TLR4 knockout alleviated tubular injury and interstitial macrophages infiltration, improved impaired renal dysfunction, and decreased the expressions of active N-terminal of GSDMD(GSDMD-N), cleaved caspase-1(cl-caspase-1) and cleaved caspase-3(cl-caspase-3) in T2DKD mice. TLR4 inhibition reduced HG-induced pyroptosis and apoptosis level in HK-2 cells, while GSDMD up-regulation increased pyroptosis rate and decreased apoptosis rate. TLR4 could exacerbate tubular injury and fibrosis via GSDMD-mediated canonical pyroptosis pathway in T2DKD. Activation of GSDMD could inhibit apoptosis and activate pyroptosis, which may involve the potential switch mechanism between TLR4-mediated pyroptosis and apoptosis in T2DKD.
Sections du résumé
BACKGROUND
Toll-like receptor 4 (TLR4) mediated pathway plays a pivotal role in promoting tubulointerstitial inflammation and contributes to the progression in type 2 diabetic kidney disease (T2DKD). As the first identified key pyroptosis executor, gasdermin D (GSDMD) is activated by caspases and might be the key protein to switch apoptosis to pyroptosis. It remains unclear that role of TLR4 on canonical pyroptosis pathway, and whether GSDMD is involved in switching from apoptosis to pyroptosis in the TLR4-related tubular injury in T2DKD.
METHODS
Immunohistochemistry staining was used to detect the expression of pyroptosis-related proteins in renal tissues of T2DKD patients. T2DKD models was induced in TLR4 knockout (TLR4
RESULTS
The expression levels of caspase-1, GSDMD, IL-18 and IL-1β were increased in renal biopsy tissues of T2DKD patients and GSDMD expression was positively correlated with tubular injury. Silencing GSDMD attenuated HG-induced IL-18, IL-1β, FN and α-SMA, and reduced pyroptotic cells rate in HK-2 cells. Up-regulation of GSDMD inhibited HG-induced expression of Bax and cleaved caspase-3 and reduced apoptosis rate. TLR4 knockout alleviated tubular injury and interstitial macrophages infiltration, improved impaired renal dysfunction, and decreased the expressions of active N-terminal of GSDMD(GSDMD-N), cleaved caspase-1(cl-caspase-1) and cleaved caspase-3(cl-caspase-3) in T2DKD mice. TLR4 inhibition reduced HG-induced pyroptosis and apoptosis level in HK-2 cells, while GSDMD up-regulation increased pyroptosis rate and decreased apoptosis rate.
CONCLUSIONS
TLR4 could exacerbate tubular injury and fibrosis via GSDMD-mediated canonical pyroptosis pathway in T2DKD. Activation of GSDMD could inhibit apoptosis and activate pyroptosis, which may involve the potential switch mechanism between TLR4-mediated pyroptosis and apoptosis in T2DKD.
Identifiants
pubmed: 35809639
pii: S0003-9861(22)00231-4
doi: 10.1016/j.abb.2022.109347
pii:
doi:
Substances chimiques
Gsdmd protein, mouse
0
Interleukin-18
0
Intracellular Signaling Peptides and Proteins
0
Phosphate-Binding Proteins
0
Pore Forming Cytotoxic Proteins
0
RNA, Small Interfering
0
Tlr4 protein, mouse
0
Toll-Like Receptor 4
0
bcl-2-Associated X Protein
0
Caspase 3
EC 3.4.22.-
Caspases
EC 3.4.22.-
Caspase 1
EC 3.4.22.36
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109347Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.