PEA3 protects against gentamicin nephrotoxicity: role of mitochondrial dysfunction

Toxin-induced nephrotoxicity is one of the major causes leading to the acute kidney injury (AKI). Among these nephrotoxic toxins, gentamicin can induce AKI with elusive mechanisms. Emerging evidence demonstrated that PEA3 (polyomavirus enhancer activator 3) contributed to the nephrogenesis, while its role in AKI remains unknown. Thus, this study was to investigate the role of PEA3 in gentamicin nephrotoxicity, as well as the underlying mechanisms. In rats, gentamicin treatment (200 mg/kg twice per day) for two days induced remarkable kidney injury with a peak damage on day 5 evaluated by the tubular injury score, proteinuria, and tubular injury markers of NGAL and KIM-1. In parallel with the tubular injury, PEA3 protein and mRNA expressions were significantly upregulated by gentamicin and peaked on day 5. To define the role of PEA3 in gentamicin nephrotoxicity, proximal tubule cells were transfected with PEA3 plasmid with or without gentamicin treatment (1 mg/ml). Notably, overexpression of PEA3 attenuated gentamicin-induced cell injury shown by the ameliorated cell apoptosis and NGAL and KIM-1 upregulation. Meantime, gentamicin caused severe mitochondrial dysfunction, which was largely normalized by PEA3 overexpression. In contrast, silencing PEA3 by a siRNA strategy further deteriorated gentamicin-induced cell apoptosis and mitochondrial dysfunction. In sum, PEA3 protected against gentamicin nephrotoxicity possibly via a mitochondrial mechanism.