Journal
ARCHIVES OF TOXICOLOGY
Volume 91, Issue 10, Pages 3225-3245Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-017-1942-9
Keywords
Unfolded protein response; Transition metal toxicity; Lysenin; Laurdan; Lysosomal membrane permeabilization
Categories
Funding
- Center for Biomedical Training and Research (ZBAF) of the University of Witten/Herdecke
- Deutsche Forschungsgemeinschaft [TH345/11-1]
- BMBF [01DN16039]
- Max Kade Foundation
- CONACYT (Consejo Nacional de Ciencia y Tecnologia, Mexico) [235537]
- NSERC Discovery grant
- PhD program Biomedicine, Witten/Herdecke University
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The renal proximal tubule (PT) is the major target of cadmium (Cd2+) toxicity where Cd2+ causes stress and apoptosis. Autophagy is induced by cell stress, e.g., endoplasmic reticulum (ER) stress, and may contribute to cell survival or death. The role of autophagy in Cd2+-induced nephrotoxicity remains unsettled due to contradictory results and lack of evidence for autophagic machinery damage by Cd2+. Cd2+-induced autophagy in rat kidney PT cell line NRK-52E and its role in cell death was investigated. Increased LC3-II and decreased p62 as autophagy markers indicate rapid induction of autophagic flux by Cd2+ (5-10 mu M) after 1 h, accompanied by ER stress (increased p-PERK, p-eIF2 alpha, CHOP). Cd2+ exposure exceeding 3 h results in p62/LC3-II accumulation, but diminished effect of lysosomal inhibitors (bafilomycin A1, pepstatin A + E-64d) on p62/LC3-II levels, indicating decreased autophagic flux and cargo degradation. At 24 h exposure, Cd2+ ( 5-25 mu M) activates intrinsic apoptotic pathways ( Bax/Bcl-2, PARP-1), which is not evident earlier (<= 6 h) although cell viability by MTT assay is decreased. Autophagy inducer rapamycin ( 100 nM) does not overcome autophagy inhibition or Cd2+-induced cell viability loss. The autophagosome-lysosome fusion inhibitor liensinine ( 5 mu M) increases CHOP and Bax/Bcl-2-dependent apoptosis by low Cd2+ stress, but not by high Cd2+. Lysosomal instability by - Cd2+ ( 5 mu M; 6 h) is indicated by increases in cellular sphingomyelin and membrane fluidity and decreases in cathepsins and LAMP1. The data suggest dual and temporal impact of Cd2+ on autophagy: Low but - Cd2+ stress accrual disrupts autophagic flux and lysosomal stability, possibly resulting in lysosomal cell death.
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