The Protective Effect of Omeprazole on Vancomycin Cytotoxicity in HK-2 Cells and Renal Injury in Rats.

Abstract

Objective: Vancomycin is the first-line treatment for MRSA infection, and high plasma concentration can cause nephrotoxicity. The aim of the study was to determine the correlation between intracellular vancomycin concentration and HK-2 cytotoxicity and explore omeprazole's protective effect. Methods: The activity of HK-2 cells was detected, HPLC method was established and verified, and the vancomycin concentrations in the intracellular and extracellular fluids of HK-2 cells were determined. Western blot was used to investigate the expressions of P-glycoprotein (P-gp) and organic cation transporter-2 (OCT-2) transporters. Blood urea nitrogen (BUN), blood creatinine (CRE), N-acetyl-β-d-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) of rats in the vancomycin group and drug combination group were determined; the kidney tissue pathological examination and renal injury score were performed. Results: The HPLC method met the requirements for biological sample determination. The cytotoxicity of vancomycin in HK-2 cells was concentration-dependent within 1-20 mg/mL; omeprazole could reduce the intracellular accumulation of vancomycin. Western blot assay confirmed that omeprazole increased intracellular vancomycin efflux by upregulating P-gp expression and inhibited its intracellular transport by downregulating OCT-2 expression. Vancomycin increased renal function indicators and pathological injury score in rats, while there was a significant decrease in the drug combination group, together with alleviated renal tissue damage. Conclusion: Intracellular accumulation of vancomycin can cause damage to HK-2 cells and induce vancomycin-related nephrotoxicity in rats. Omeprazole can reduce vancomycin cytotoxicity by upregulating P-gp expression and inhibiting OCT-2 expression.