Activation of Nrf2 by cadmium and its role in protection against cadmium-induced apoptosis in rat kidney cells
- Department of Biomedical and Pharmaceutical Science, and Center for Molecular Toxicology, College of Pharmacy, University of Rhode Island, Kingston, RI 02881 (United States)
Kidney is the primary target organ in chronic cadmium (Cd) toxicity, and oxidative stress plays an important role in this process. The nuclear transcription factor Nrf2 binds to antioxidant response elements (AREs) and regulates genes involved in protecting cells from oxidative damage. Whether kidney cells respond to Cd by activating Nrf2 is unknown. This study was designed to examine the Cd-induced activation of Nrf2 transcriptional activity in a stable rat kidney cell line, NRK-52E, and to investigate the protection this might offer against apoptosis. The cells were treated with 5-20 muM CdCl{sub 2} for 5 h, followed by a recovery period of up to 24 h. A concentration-dependent increase (up to 2.9-fold) in the level of reactive oxygen species was noted upon termination of 5-h Cd treatment. The Nrf2-ARE binding activity also increased and peaked (6.1-fold) at 10 muM Cd concentration. Time-course study revealed that the binding activity increased at 1 h of Cd treatment and peaked 2 h post Cd treatment. Apoptosis was detected 6 h post treatment with Cd and a concentration- and time-dependent increase in the apoptotic cell population occurred during the next 18 h. Over-expression of Nrf2 by transient transfection conferred resistance against Cd-induced apoptosis. Conversely, suppression of Nrf2 expression by specific siRNA resulted in greater sensitivity of the cells to Cd by decreasing the levels of two antioxidant enzymes, hemeoxygenase-1 and glutamate-cysteine ligase. Taken together, these results suggest that in kidney cells the activation of Nrf2 is an adaptive intracellular response to Cd-induced oxidative stress, and that Nrf2 is protective against Cd-induced apoptosis.
- OSTI ID:
- 21344789
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 241, Issue 1; Other Information: DOI: 10.1016/j.taap.2009.07.038; PII: S0041-008X(09)00330-5; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTIOXIDANTS
APOPTOSIS
CADMIUM
CADMIUM CHLORIDES
CYSTEINE
DAMAGE
GENES
HEME
INHIBITION
KIDNEYS
LIGASES
OXYGENASES
RATS
RNA
STRESSES
TRANSCRIPTION FACTORS
AMINO ACIDS
ANIMALS
BODY
CADMIUM COMPOUNDS
CADMIUM HALIDES
CARBOXYLIC ACIDS
CHLORIDES
CHLORINE COMPOUNDS
ELEMENTS
ENZYMES
HALIDES
HALOGEN COMPOUNDS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
MAMMALS
METALS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXIDOREDUCTASES
PIGMENTS
PORPHYRINS
PROTEINS
RODENTS
THIOLS
VERTEBRATES