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Live and Let Die: Roles of Autophagy in Cadmium Nephrotoxicity

by 1,* and 1,2
1
Institute of Physiology, Pathophysiology & Toxicology, Center for Biomedical Training and Research (ZBAF), Stockumer Str. 12, University of Witten/Herdecke, 58453 Witten, Germany
2
Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Wayne Briner
Toxics 2015, 3(2), 130-151; https://doi.org/10.3390/toxics3020130
Received: 15 March 2015 / Revised: 30 March 2015 / Accepted: 3 April 2015 / Published: 13 April 2015
(This article belongs to the Collection Heavy Metals Toxicology)
The transition metal ion cadmium (Cd2+) is a significant environmental contaminant. With a biological half-life of ~20 years, Cd2+ accumulates in the kidney cortex, where it particularly damages proximal tubule (PT) cells and can result in renal fibrosis, failure, or cancer. Because death represents a powerful means by which cells avoid malignant transformation, it is crucial to clearly identify and understand the pathways that determine cell fate in chronic Cd2+ nephrotoxicity. When cells are subjected to stress, they make a decision to adapt and survive, or—depending on the magnitude and duration of stress—to die by several modes of death (programmed cell death), including autophagic cell death (ACD). Autophagy is part of a larger system of intracellular protein degradation and represents the channel by which organelles and long-lived proteins are delivered to the lysosome for degradation. Basal autophagy levels in all eukaryotic cells serve as a dynamic physiological recycling system, but they can also be induced by intra- or extracellular stress and pathological processes, such as endoplasmic reticulum (ER) stress. In a context-dependent manner, autophagy can either be protective and hence contribute to survival, or promote death by non-apoptotic or apoptotic pathways. So far, the role of autophagy in Cd2+-induced nephrotoxicity has remained unsettled due to contradictory results. In this review, we critically survey the current literature on autophagy in Cd2+-induced nephrotoxicity in light of our own ongoing studies. Data obtained in kidney cells illustrate a dual and complex function of autophagy in a stimulus- and time-dependent manner that possibly reflects distinct outcomes in vitro and in vivo. A better understanding of the context-specific regulation of cell fate by autophagy may ultimately contribute to the development of preventive and novel therapeutic strategies for acute and chronic Cd2+ nephrotoxicity. View Full-Text
Keywords: unfolded protein response; transition metal; cadmium; apoptosis; autophagosome; acute kidney injury; malignant transformation; tunicamycin; rapamycin; mTORC unfolded protein response; transition metal; cadmium; apoptosis; autophagosome; acute kidney injury; malignant transformation; tunicamycin; rapamycin; mTORC
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MDPI and ACS Style

Thévenod, F.; Lee, W.-K. Live and Let Die: Roles of Autophagy in Cadmium Nephrotoxicity. Toxics 2015, 3, 130-151. https://doi.org/10.3390/toxics3020130

AMA Style

Thévenod F, Lee W-K. Live and Let Die: Roles of Autophagy in Cadmium Nephrotoxicity. Toxics. 2015; 3(2):130-151. https://doi.org/10.3390/toxics3020130

Chicago/Turabian Style

Thévenod, Frank, and Wing-Kee Lee. 2015. "Live and Let Die: Roles of Autophagy in Cadmium Nephrotoxicity" Toxics 3, no. 2: 130-151. https://doi.org/10.3390/toxics3020130

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