Abstract
Vancomycin, a widely used antibiotic, often induces nephrotoxicity, however, the molecular targets and underlying mechanisms of this side effect remain unclear. The present study aimed to examine molecular interactome and analyze the signaling pathways related to the vancomycin-induced nephrotoxicity in human proximal tubule epithelial HK-2 cells using the stable isotope labeling by amino acids in cell culture (SILAC) approach. The quantitative proteomic study revealed that there were at least 492 proteins interacting with vancomycin and there were 290 signaling pathways and cellular functions potentially regulated by vancomycin in HK-2 cells. These proteins and pathways played a critical role in the regulation of cell cycle, apoptosis, autophagy, EMT, and ROS generation. These findings suggest that vancomycin-induced proteomic responses in HK-2 cells involvefunctional proteins and pathways that regulate cell cycle, apoptosis, autophagy, and redox homeostasis. This is the first systemic study revealed the networks of signaling pathways and proteomic responses to vancomycin treatment in HK-2 cells, and the data may be used to discriminate the molecular and clinical subtypes and to identify new targets and biomarkers for vancomycin-induced nephrotoxic effect. Further studies are warranted to explore the potential of quantitative proteomic analysis in the identification of new targets and biomarkers for drug-induced renal toxicity.
Highlights
Neonatal sepsis is common and is a major cause of morbidity and mortality [1]
In order to uncover the comprehensive and global understanding on the effect of vancomycin, we investigated the molecular targets of vancomycin in human proximal tubule epithelial HK-2 cells with a focus on cell cycle, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) pathways
We performed a SILAC-based proteomic study to quantitatively determine the interactome of vancomycin in HK-2 cells treated with vancomycin at 50 μg/mL
Summary
Vancomycin is the preferred treatment for several neonatal staphylococcal infections. It remains the primary antibiotic treatment for multi-resistant Gram-positive infections, such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium [2]. Vancomycin has historically been linked to various toxicities, in particular nephrotoxicity, it was largely attributed to drug impurities in early formulations [4,5]. The incidence of such toxicities was drastically reduced after refinement of purification methods and the risk of nephrotoxicity was considered relatively low at less than 5% [5,6,7]
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