Gentamicin is a used
antibiotic that causes nephrotoxicity in 10-20% of treatment periods, which limits its use considerably. Our results have shown that
cilastatin may be a promising therapeutic alternative in toxin-induced
acute kidney injury (AKI). Here, we investigated its potential use as a nephroprotector against
gentamicin-induced AKI in vitro and in vivo. Porcine renal cells and rats were treated with
gentamicin and/or
cilastatin. In vivo nephrotoxicity was analyzed by measuring
biochemical markers and renal morphology. Different apoptotic, oxidative and inflammatory parameters were studied at cellular and systemic levels.
Megalin, mainly responsible for the entry of
gentamicin into the cells, was also analyzed. Results show that
cilastatin protects cells from
gentamicin-induced AKI.
Cilastatin decreased
creatinine, BUN, kidney injury molecule-1 (KIM-1) and severe morphological changes previously increased by
gentamicin in rats. The interference of
cilastatin with
lipid rafts cycling leads to decreased expression of
megalin, and therefore
gentamicin uptake and myeloid bodies, resulting in a decrease of apoptotic, oxidative and inflammatory events. Moreover,
cilastatin did not prevent bacterial death by
gentamicin.
Cilastatin reduced
gentamicin-induced AKI by preventing key steps in the amplification of the damage, which is associated to the disruption of
megalin-
gentamicin endocytosis. Therefore,
cilastatin might represent a novel therapeutic tool in the prevention and treatment of
gentamicin-induced AKI in the clinical setting.