期刊
TOXICS
卷 3, 期 2, 页码 130-151出版社
MDPI
DOI: 10.3390/toxics3020130
关键词
unfolded protein response; transition metal; cadmium; apoptosis; autophagosome; acute kidney injury; malignant transformation; tunicamycin; rapamycin; mTORC
资金
- Deutsche Forschungsgemeinschaft [TH345]
- Max Kade Foundation
- Center for Biomedical Training and Research ZBAF
The transition metal ion cadmium (Cd2+) is a significant environmental contaminant. With a biological half-life of similar to 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.
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