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|Title: ||Glutathione and mitochondria determine acute defense responses and adaptive processes in cadmium-induced oxidative stress and toxicity of the kidney|
|Authors: ||Ravindran Nair, Ambily|
|Issue Date: ||2015|
|Citation: ||ARCHIVES OF TOXICOLOGY, 89 (12), p. 2273-2289|
|Abstract: ||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 µM, 24 h) and in vivo in Fischer 344 rats for sub-chronic Cd2+ toxicity (1 mg/kg CdCl2 subcutaneously, 13 days). Whereas 30 µM
Cd2+ caused ~50 % decrease in cell viability, apoptosis peaked at 10 µM 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 Pparγ and mitochondrial DNA was increased, and cellular ATP was unaffected with Cd2+ (1–10 µM). 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 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 Cd2+ in renal PTCs as well as in adaptive processes associated with chronic renal Cd2+ toxicity.|
|Notes: ||Cuypers, A (reprint author), Hasselt Univ, Ctr Environm Sci, Environm Biol, Diepenbeek, Belgium.
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|ISI #: ||000366155200008|
|Type: ||Journal Contribution|
|Validation: ||ecoom, 2017|
|Appears in Collections: ||Research publications|
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