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Glutathione and mitochondria determine acute defense responses and adaptive processes in cadmium-induced oxidative stress and toxicity of the kidney.
- Source :
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Archives of toxicology [Arch Toxicol] 2015 Dec; Vol. 89 (12), pp. 2273-89. Date of Electronic Publication: 2014 Nov 12. - Publication Year :
- 2015
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Abstract
- Cadmium (Cd(2+)) induces oxidative stress that ultimately defines cell fate and pathology. Mitochondria are the main energy-producing organelles in mammalian cells, but they also have a central role in formation of reactive oxygen species, cell injury, and death signaling. As the kidney is the major target in Cd(2+) toxicity, the roles of oxidative signature and mitochondrial function and biogenesis in Cd(2+)-related stress outcomes were investigated in vitro in cultured rat kidney proximal tubule cells (PTCs) (WKPT-0293 Cl.2) for acute Cd(2+) toxicity (1-30 µM, 24 h) and in vivo in Fischer 344 rats for sub-chronic Cd(2+) toxicity (1 mg/kg CdCl2 subcutaneously, 13 days). Whereas 30 µM Cd(2+) caused ~50 % decrease in cell viability, apoptosis peaked at 10 µM Cd(2+) in PTCs. A steep, dose-dependent decline in reduced glutathione (GSH) content occurred after acute exposure and an increase of the oxidized glutathione (GSSG)/GSH ratio. Quantitative PCR analyses evidenced increased antioxidative enzymes (Sod1, Gclc, Gclm), proapoptotic Bax, metallothioneins 1A/2A, and decreased antiapoptotic proteins (Bcl-xL, Bcl-w). The positive regulator of mitochondrial biogenesis Pparγ and mitochondrial DNA was increased, and cellular ATP was unaffected with Cd(2+) (1-10 µM). In vivo, active caspase-3, and hence apoptosis, was detected by FLIVO injection in the kidney cortex of Cd(2+)-treated rats together with an increase in Bax mRNA. However, antiapoptotic genes (Bcl-2, Bcl-xL, Bcl-w) were also upregulated. Both GSSG and GSH increased with chronic Cd(2+) exposure with no change in GSSG/GSH ratio and augmented expression of antioxidative enzymes (Gpx4, Prdx2). Mitochondrial DNA, mitofusin 2, and Pparα were increased indicating enhanced mitochondrial biogenesis and fusion. Hence, these results demonstrate a clear involvement of higher mitochondria copy numbers or mass and mitochondrial function in acute defense against oxidative stress induced by Cd(2+) in renal PTCs as well as in adaptive processes associated with chronic renal Cd(2+) toxicity.
- Subjects :
- Animals
Apoptosis drug effects
Cadmium Chloride administration & dosage
Caspase 3 metabolism
Cell Line
Dose-Response Relationship, Drug
Female
Kidney drug effects
Kidney pathology
Kidney Tubules, Proximal drug effects
Kidney Tubules, Proximal pathology
Male
Mitochondria metabolism
Rats
Rats, Inbred F344
Rats, Inbred WKY
Reactive Oxygen Species metabolism
Cadmium Chloride toxicity
Glutathione metabolism
Mitochondria drug effects
Oxidative Stress drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0738
- Volume :
- 89
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Archives of toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 25388156
- Full Text :
- https://doi.org/10.1007/s00204-014-1401-9