PMID- 27613716
OWN - NLM
STAT- MEDLINE
DCOM- 20180116
LR  - 20201209
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 154
IP  - 2
DP  - 2016 Dec
TI  - Transient Proteotoxicity of Bacterial Virulence Factor Pyocyanin in Renal Tubular 
      Epithelial Cells Induces ER-Related Vacuolation and Can Be Efficiently Modulated 
      by Iron Chelators.
PG  - 403-415
AB  - Persistent infections of biofilm forming bacteria, such as Pseudomonas 
      aeruginosa, are common among human populations, due to the bacterial resistance 
      to antibiotics and other adaptation strategies, including release of cytotoxic 
      virulent factors such as pigment pyocyanin (PCN). Urinary tract infections harbor 
      P. aeruginosa strains characterized by the highest PCN-producing capacity, yet no 
      information is available on PCN cytotoxicity mechanism in kidney. We report here 
      that renal tubular epithelial cell (RTEC) line NRK-52E responds to PCN treatments 
      with paraptosis-like activity features. Specifically, PCN-treated cells 
      experienced dilation of endoplasmic reticulum (ER) and an extensive development 
      of ER-derived vacuoles after about 8 h. This process was accompanied with 
      hyper-activation of proteotoxic stress-inducible transcription factors Nrf2, 
      ATF6, and HSF-1. The cells could be rescued by withdrawal of PCN from the culture 
      media before the vacuoles burst and cells die of non-programmed necrosis after 
      about 24-30 h. The paraptosis-like activity was abrogated by co-treatment of the 
      cells with metal-chelating antioxidants. A microscopic examination of cells 
      co-treated with PCN and agents aiming at a variety of the cellular stress 
      mediators and pathways have identified iron as a single most significant 
      co-factor of the PCN cytotoxicity in the RTECs. Among biologically relevant metal 
      ions, low micromolar Fe(2+ )specifically mediated anaerobic oxidation of 
      glutathione by PCN, but catechol derivatives and other strong iron complexing 
      agents could inhibit the reaction. Our data suggest that iron chelation could be 
      considered as a supplementary treatment in the PCN-positive infections.
CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the Society 
      of Toxicology.
FAU - Mossine, Valeri V
AU  - Mossine VV
AD  - Department of Biochemistry mossinev@missouri.edu.
AD  - Experiment Station Chemical Labs, University of Missouri, Columbia, Missouri 
      65211.
FAU - Waters, James K
AU  - Waters JK
AD  - Experiment Station Chemical Labs, University of Missouri, Columbia, Missouri 
      65211.
FAU - Chance, Deborah L
AU  - Chance DL
AD  - Department of Molecular Microbiology and Immunology.
AD  - Department of Child Health, University of Missouri, Columbia, Missouri 65211.
FAU - Mawhinney, Thomas P
AU  - Mawhinney TP
AD  - Department of Biochemistry.
AD  - Experiment Station Chemical Labs, University of Missouri, Columbia, Missouri 
      65211.
AD  - Department of Child Health, University of Missouri, Columbia, Missouri 65211.
LA  - eng
GR  - P50 AT006273/AT/NCCIH NIH HHS/United States
PT  - Journal Article
DEP - 20160909
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (ATF6 protein, human)
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (HSF1 protein, human)
RN  - 0 (Heat Shock Transcription Factors)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 9OQM399341 (Pyocyanine)
RN  - E1UOL152H7 (Iron)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
EIN - Toxicol Sci. 2017 Feb;155(2):512. PMID: 28123001
MH  - Activating Transcription Factor 6/genetics/metabolism
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Endoplasmic Reticulum/*drug effects/metabolism/pathology
MH  - Epithelial Cells/*drug effects/metabolism/pathology
MH  - Glutathione/metabolism
MH  - Heat Shock Transcription Factors/genetics/metabolism
MH  - Iron/*metabolism
MH  - Iron Chelating Agents/*pharmacology
MH  - Kidney Tubules/*drug effects/metabolism/pathology
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Necrosis
MH  - Oxidative Stress/drug effects
MH  - Pseudomonas aeruginosa/metabolism/*pathogenicity
MH  - Pyocyanine/chemical synthesis/*pharmacology
MH  - Rats
MH  - Time Factors
MH  - Unfolded Protein Response/drug effects
MH  - Vacuoles/*drug effects/metabolism/pathology
MH  - Virulence
PMC - PMC5139071
OTO - NOTNLM
OT  - Pyocyanin
OT  - endoplasmic reticulum stress.
OT  - glutathione
OT  - iron
OT  - proteotoxic stress response
OT  - renal tubular epithelial cells
EDAT- 2016/09/11 06:00
MHDA- 2018/01/18 06:00
PMCR- 2016/09/09
CRDT- 2016/09/11 06:00
PHST- 2016/09/11 06:00 [pubmed]
PHST- 2018/01/18 06:00 [medline]
PHST- 2016/09/11 06:00 [entrez]
PHST- 2016/09/09 00:00 [pmc-release]
AID - kfw174 [pii]
AID - 10.1093/toxsci/kfw174 [doi]
PST - ppublish
SO  - Toxicol Sci. 2016 Dec;154(2):403-415. doi: 10.1093/toxsci/kfw174. Epub 2016 Sep 
      9.