Epigenetic modifiers exacerbate oxidative stress in renal proximal tubule cells

Area of Science:

• Cell biology
• Toxicology
• Pharmacology

Background:

• Anticancer drugs can increase reactive oxygen species (ROS) production, potentially causing nephrotoxicity.
• Epigenetic modifiers are a class of anticancer drugs with potential kidney toxicity.

Purpose of the Study:

• To investigate the effects of two epigenetic modifiers, trichostatin A (TSA) and 5-aza-deoxycytidine (5AZA), on ROS production and renal cell injury.
• To determine if the antioxidant N-acetyl-cysteine (NAC) can mitigate the observed cell injury.

Main Methods:

• Mouse renal proximal tubule cells were treated with TSA and 5AZA, alone or with hydrogen peroxide (H2O2).
• ROS production and lactate dehydrogenase (LDH) release were measured.
• The effect of NAC on LDH release was assessed.
• CREB-mediated transcription was analyzed.

Main Results:

• Both TSA and 5AZA increased mitochondrial ROS production and LDH release.
• NAC treatment abolished the LDH release induced by these agents.
• CREB-mediated transcription, crucial for proximal tubule cell survival, was attenuated by TSA and 5AZA.

Conclusions:

• The ROS-inducing properties of TSA and 5AZA may contribute to their in vivo nephrotoxicity.
• Mechanisms of injury involve impaired pro-survival signaling and/or activation of death pathways linked to mitochondrial ROS release.