JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats

Abstract

The present study aimed to investigate the regulation of JBP485 on the expressions of renal organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp), which can accelerate the renal excretion of accumulated endogenous toxins to attenuate vancomycin-induced nephrotoxicity (VIN) in rats. Vancomycin suppressed the mRNA and protein expressions of Oat1, Oat3, Oct2, Mrp2 and P-gp to reduce the renal excretion of endogenous toxins (e.g. indoxyl sulfate). However, JBP485 could reverse these effects and improved the pathological condition and morphology of rat kidney with a decrease in wet weight. Moreover, JBP485 decreased the number of apoptosis cells in TUNEL staining as well as reversed the decreased expression of B-cell lymphoma-2 (Bcl-2) and the increased expressions of Bcl-2-like protein 4 (Bax) and Caspase-3 in rat kidney. In addition, JBP485 also increased the level of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in rat kidney. But JBP485 did not affect the plasma concentrations of vancomycin. In conclusion, the mechanism of VIN might be involved in, at least in part, suppressing the expressions of Oat1, Oat3, Oct2, Mrp2 and P-gp, and JBP485 could attenuate VIN in rats.

Keywords: Endogenous toxins; JBP485; Nephrotoxicity; Transporter; Vancomycin.