[en] Gentamicin, an aminoglycoside used to treat severe bacterial infections, may cause acute renal failure. In the renal cell line LLC-PK1, gentamicin accumulates in lysosomes, induces alterations of their permeability, and triggers the mitochondrial pathway of apoptosis via activation of caspase-9 and -3 and changes in Bcl-2 family proteins. Early ROS production in lysosomes has been associated with gentamicin induced lysosomal membrane permeabilization. In order to better understand the multiple interconnected pathways of gentamicin-induced apoptosis and ensuing renal cell toxicity, we investigated the effect of gentamicin on p53 and p21 levels. We also studied the potential effect of gentamicin on proteasome by measuring the chymotrypsin-, trypsin- and caspase-like activities, and on endoplasmic reticulum by determining phopho-eIF2alpha, caspase-12 activation and GRP78 and 94. We observed an increase in p53 levels, which was dependent on ROS production. Accumulation of p53 resulted in accumulation of p21 and of phospho-eIF2alpha. These effects could be related to an impairment of proteasome as we demonstrated an inhibition of trypsin-and caspase-like activities. Moderate endoplasmic reticulum stress could also participate to cellular toxicity induced by gentamicin, with activation of caspase-12 without change in GRP74 and GRP98. All together, these data provide new mechanistic insights into the apoptosis induced by aminoglycoside antibiotics on renal cell lines.
Research Center/Unit :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Denamur, Sophie
Boland, Lidvine
Beyaert, Maxime
Verstraeten, Sandrine L.
Fillet, Marianne ; Université de Liège > Département de pharmacie > Analyse des médicaments
Tulkens, Paul M.
Bontemps, Francoise
Mingeot-Leclercq, Marie-Paule
Language :
English
Title :
Subcellular mechanisms involved in apoptosis induced by aminoglycoside antibiotics: Insights on p53, proteasome and endoplasmic reticulum.
Publication date :
2016
Journal title :
Toxicology and Applied Pharmacology
ISSN :
0041-008X
eISSN :
1096-0333
Publisher :
Elsevier, Atlanta, United States - New York
Volume :
309
Pages :
24-36
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2016 Elsevier Inc. All rights reserved.
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