Journal
ARCHIVES OF TOXICOLOGY
Volume 89, Issue 12, Pages 2273-2289Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-014-1401-9
Keywords
Oxidative stress; Metallothionein; Antioxidative enzymes; Mitochondrial DNA content; Apoptosis
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Funding
- Hasselt University [BOF (Bijzonder onderzoeksfonds)] [BOF08G01]
- Deutsche Forschungsgemeinschaft [DFG TH345/11-1]
- tUL-impulsfinanciering
- Methusalem project [08M03VGRJ]
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Cadmium (Cd2+) 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 Cd2+ toxicity, the roles of oxidative signature and mitochondrial function and biogenesis in Cd2+-related stress outcomes were investigated in vitro in cultured rat kidney proximal tubule cells (PTCs) (WKPT-0293 Cl.2) for acute Cd2+ toxicity (1-30 A mu M, 24 h) and in vivo in Fischer 344 rats for sub-chronic Cd2+ toxicity (1 mg/kg CdCl2 subcutaneously, 13 days). Whereas 30 A mu M Cd2+ caused 50 % decrease in cell viability, apoptosis peaked at 10 A mu M Cd2+ 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 Ppar gamma and mitochondrial DNA was increased, and cellular ATP was unaffected with Cd2+ (1-10 A mu M). In vivo, active caspase-3, and hence apoptosis, was detected by FLIVO injection in the kidney cortex of Cd2+-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 Cd2+ exposure with no change in GSSG/GSH ratio and augmented expression of antioxidative enzymes (Gpx4, Prdx2). Mitochondrial DNA, mitofusin 2, and Ppar alpha 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 Cd2+ in renal PTCs as well as in adaptive processes associated with chronic renal Cd2+ toxicity.
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