Activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress contributes to lead-induced nephrotoxicity.
Activating Transcription Factor 4
/ metabolism
Animals
Apoptosis
/ drug effects
Autophagy
/ drug effects
Cells, Cultured
Endoplasmic Reticulum Stress
/ drug effects
Eukaryotic Initiation Factor-2
/ metabolism
Kidney Tubules, Proximal
/ drug effects
Lead
/ toxicity
Phenylbutyrates
/ pharmacology
Rats, Sprague-Dawley
Transcription Factor CHOP
/ metabolism
Tunicamycin
/ pharmacology
eIF-2 Kinase
/ genetics
Apoptosis
Autophagy
Lead
PERK-eIF2α-ATF4-CHOP pathway
Proximal tubular cells
Journal
Biochimica et biophysica acta. Molecular cell research
ISSN: 1879-2596
Titre abrégé: Biochim Biophys Acta Mol Cell Res
Pays: Netherlands
ID NLM: 101731731
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
25
07
2018
revised:
07
11
2018
accepted:
01
12
2018
pubmed:
12
12
2018
medline:
10
9
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
Lead (Pb) is a known nephrotoxicant that causes damage to proximal tubular cells. PERK pathway plays an important role in the pathogenesis of renal diseases, but its role in Pb-induced nephrotoxicity remains largely unknown. In this study, data showed that Pb could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eIF2α-ATF4-CHOP axis in primary rat proximal tubular (rPT) cells, indicating the activation of PERK-eIF2α-ATF4-CHOP pathway due to excessive ER stress. Pb-activated PERK pathway can be effectively inhibited by 4-phenylbutyric acid and PERK gene silencing, respectively; whereas continuously up-regulated by tunicamycin (TM) treatment. Moreover, Pb-induced apoptosis and inhibition of autophagic flux in rPT cells were significantly augmented and aggravated by co-treatment with TM, respectively. Pharmacological or genetic inhibition of the PERK pathway results in alleviation of apoptosis and restoration of autophagy inhibition in Pb-exposed rPT cells. Mechanistically, activation of PERK-eIF2α-ATF4-CHOP axis triggered by excessive ER stress in rPT cells leads to Pb-induced apoptosis and blockage of autophagic flux, resulting in nephrotoxicity.
Identifiants
pubmed: 30528975
pii: S0167-4889(18)30213-1
doi: 10.1016/j.bbamcr.2018.12.002
pii:
doi:
Substances chimiques
Atf4 protein, rat
0
Ddit3 protein, rat
0
Eukaryotic Initiation Factor-2
0
Phenylbutyrates
0
Tunicamycin
11089-65-9
Activating Transcription Factor 4
145891-90-3
Transcription Factor CHOP
147336-12-7
Lead
2P299V784P
4-phenylbutyric acid
7WY7YBI87E
PERK kinase
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
713-726Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.