Abstract
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 the rat kidney PT cell line NRK‐52E and its role in cell death was investigated. Autophagy markers LC3‐II and p62 indicate rapid induction of autophagic flux by Cd2+ (5–10μM) after 1h, accompanied by ER stress (increased p‐PERK, p‐eIF2α, CHOP). Cd2+ exposure exceeding 3h results in p62/LC3‐II accumulation, but diminished effect of lysosomal inhibitors (bafilomycin A1, pepstatin A+E64d) on p62/LC3‐II levels, indicating decreased autophagic flux and cargo degradation. At 24h exposure, Cd2+ (5–25μM) activates intrinsic apoptotic pathways (Bax/Bcl‐2, PARP1), which are not evident earlier (≤ 6h) despite decreased cell viability by MTT assay. Autophagy inducer rapamycin (100nM) does not overcome autophagy inhibition or Cd2+‐induced cell viability loss. The autophagosome‐lysosome fusion inhibitor liensinine (5μM) increases CHOP and Bax/Bcl‐2 dependent apoptosis by low Cd2+ stress, but not by high Cd2+. Lysosomal instability by Cd2+ (5μM; 6h) is indicated by increased cellular sphingomyelin and membrane fluidity and decreased cathepsins and LAMP1.The data suggest dual and temporal impact of Cd2+ on autophagy: Low Cd2+ stress rapidly activates autophagy counteracting damage but Cd2+ stress accrual disrupts autophagic flux and lysosomal stability, possibly resulting in lysosomal cell death.Support or Funding InformationCenter for Biomedical Training and Research (ZBAF) of the University of Witten/Herdecke (F.T.), Deutsche Forschungsgemeinschaft (TH345/11‐1 to F.T.), Max Kade Foundation (W.‐K.L.), CONACYT (Consejo Nacional de Ciencia y Tecnología, Mexico) (235537 to M.P.S.‐S.), and NSERC Discovery grant (E.J.P.)
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callSimilar Papers
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
