Intermittent Exposure to Xenon Protects against Gentamicin-Induced Nephrotoxicity

Aminoglycoside antibiotics, especially gentamicin, are widely used to treat Gram-negative infections due to their efficacy and low cost. Nevertheless the use of gentamicin is limited by its major side effect, nephrotoxicity. Xenon (Xe) provided substantial organoprotective effects in acute injury of the brain and the heart and protected against renal ischemic-reperfusion injury. In this study, we investigated whether xenon could protect against gentamicin-induced nephrotoxicity. Male Wistar rats were intermittently exposed to either 70% xenon or 70% nitrogen (N(2)) balanced with 30% oxygen before and during gentamicin administration at a dose of 100 mg/kg for 7 days to model gentamicin-induced kidney injury. We observed that intermittent exposure to Xe provided morphological and functional renoprotection, which was characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress, but not a reduction in inflammation. We also found that Xe pretreatment upregulated hypoxia-inducible factor 2α (HIF-2α) and its downstream effector vascular endothelial growth factor, but not HIF-1α. With regard to the three HIF prolyl hydroxylases, Xe pretreatment upregulated prolyl hydroxylase domain-containing protein-2 (PHD2), suppressed PHD1, and had no influence on PHD3 in the rat kidneys. Pretreatment with Xe also increased the expression of miR-21, a microRNA known to have anti-apoptotic effects. These results support Xe renoprotection against gentamicin-induced nephrotoxicity.