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Protective effect of cadmium-induced autophagy in rat renal mesangial cells

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Abstract

Cadmium damages renal cells, and in particular may cause mesangial cell death by necrosis or apoptosis, depending on exposure conditions in cultured cells. However, there is an uncertainty as to whether Cd2+-induced autophagy can protect mesangial cells against these other mechanisms of cell death. We have used autophagy-incompetent mouse embryonic fibroblast (MEF) cells lacking the Atg16 gene, as well as cultured rat mesangial cells (RMC) in which Atg16 has been silenced, to examine this issue. Measuring the processing of LC3-I to LC3-II and expression of sequestosome-1 (p62), we define conditions under which RMC can be induced to undergo autophagy in response to 0–20 µM CdCl2. Similarly, Cd2+ can initiate autophagy in MEF cells. However, when autophagy is compromised, either by gene knockout in MEF cells or by RNA silencing in RMC, cell viability is decreased, and concomitantly a Cd2+ dose-dependent increase in pro-caspase-3 cleavage indicates the initiation of apoptotic cell death. In contrast to some previous reports, Cd2+-induced autophagy is not correlated with increased levels of cellular reactive oxygen species but, among a panel of kinases investigated, is suppressed by inhibition of the Jun kinase. We conclude that concentrations of Cd2+ that initiate autophagy may afford renal mesangial cells some degree of protection against other modes (apoptosis, necrosis) of cell death.

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Acknowledgements

This work was funded by Grant #418208 to DMT from the Natural Sciences and Engineering Research Council of Canada.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A8, Canada

    Hitomi Fujishiro, Ying Liu, Bilal Ahmadi & Douglas M. Templeton

  2. Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan

    Hitomi Fujishiro

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Correspondence to Douglas M. Templeton.

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Fujishiro, H., Liu, Y., Ahmadi, B. et al. Protective effect of cadmium-induced autophagy in rat renal mesangial cells. Arch Toxicol 92, 619–631 (2018). https://doi.org/10.1007/s00204-017-2103-x

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