Dapagliflozin improves early acute kidney injury induced by vancomycin in rats: Insights on activin A/miRNA-21 signaling and FOXO3a expression.

ABSTRACT

Drug-induced acute kidney injury (AKI) represents a potentially serious disorder associated with increased morbidity and mortality. The presented study investigated the ability of the oral antidiabetic agent, dapagliflozin (DAPA), to preserve the kidneys of rats subjected to vancomycin (VCM)-induced AKI. Rats were injected with VCM (400 mg/kg; i.p daily) for 7 successive days to induce AKI. Rats that received VCM were pretreated with DAPA at 5 or 10 mg/kg; p.o daily for 14 successive days. Vancomycin-treated rats depicted renal tubular damage, decline in renal function, and renal morphological alterations. Impairment of renal antioxidant machinery and propagation of renal cell apoptosis was apparent in the setting of VCM overdose. Pretreatment of VCM rats with DAPA, particularly at 10 mg/kg, effectively attenuated NADPH oxidase-4 (NOX4)-induced renal ROS, hampered activin A activation, and repressed miRNA-21/PTEN/pAKT signaling. These events were associated with impeding the expression of renal p-FOXO3a/t-FOXO3a ratio and promoting the nuclear localization of FOXO3a immnoexpression, enhancing renal antioxidant enzymes. At the same time, DAPA pretreatment improved renal function indices and alleviated the kidney injury markers, NGAL, and KIM-1, accompanied by restoring the normal renal histopathological structure. Regarding renal apoptosis, DAPA suppressed the expression of Bax/Bcl2 ratio and caspase-3. This study demonstrates that DAPA ameliorates VCM-induced AKI in rats via modulating renal oxidative stress, presumably by interfering with NOX4/activin A/miRNA-21 cascade and augmenting t-FOXO3a expression as well as dampening renal cell apoptosis.