Protection against vancomycin-associated nephrotoxicity by zileuton: role of mitochondria revealed by electron microscopic study

Vancomycin is commonly used to treat drug-resistant bacterial infections despite its potential to cause nephrotoxicity. We previously showed that zileuton can reduce vancomycin nephrotoxicity, but the intracellular mechanism(s) are not fully understood. The objective of this study was to improve our understanding of the mechanisms of nephroprotection by zileuton. Sprague-Dawley rats were administered vancomycin (200 mg/kg/day) and zileuton (4 mg/kg/day) for 3 days. Blood samples were collected to determine serum creatinine concentration. Kidneys were collected for morphologic study including comprehensive electron microscopic examination. Treatment with vancomycin alone resulted in doubling of serum creatinine. Significant tubular cell injury was noted by light microscopy. Electron microscopy further defined the nature of tubular cell injury including tubular cell necrosis, cytoplasmic vacuolization, endoplasmic reticulum dilation, and aggregation of granular/fibrillary material. Distinct mitochondrial changes included swelling, appearance of crowded/disorganized cristae, punctuated electron dense matrices, and large lysosomes containing substructures consistent with abnormal mitochondria. These changes were markedly attenuated with adjuvant zileuton. Our findings indicate that mitochondrial injury is a major mechanism of vancomycin-associated nephrotoxicity, and restoration of mitochondrial morphology is associated with nephroprotection by zileuton. These findings would be valuable for nephroprotective strategies to reduce vancomycin-associated nephrotoxicity, allowing optimal vancomycin use to treat bacterial infections.