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A SILAC-Based Approach Elicits the Proteomic Responses to Vancomycin-Associated Nephrotoxicity in Human Proximal
1Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China. lizhiling22@163.com.
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.
Insights
Vancomycin-induced kidney damage involves complex molecular interactions. This study identifies key proteins and pathways, offering potential biomarkers for vancomycin nephrotoxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Vancomycin is a critical antibiotic but can cause nephrotoxicity, with unclear molecular mechanisms.
- Understanding vancomycin's molecular targets is crucial for mitigating kidney damage.
Purpose of the Study:
- To investigate the molecular interactome and signaling pathways of vancomycin-induced nephrotoxicity.
- To identify potential biomarkers for vancomycin-induced kidney injury.
Main Methods:
- Utilized Stable Isotope Labeling by Amino acids in Cell culture (SILAC) for quantitative proteomic analysis.
- Examined vancomycin's effects on human proximal tubule epithelial HK-2 cells.
Main Results:
- Identified at least 492 proteins interacting with vancomycin.
- Revealed 290 signaling pathways and cellular functions regulated by vancomycin.
- Observed involvement of proteins and pathways regulating cell cycle, apoptosis, autophagy, EMT, and ROS generation.
Conclusions:
- Vancomycin nephrotoxicity involves complex proteomic responses affecting cell cycle, apoptosis, autophagy, and redox homeostasis.
- This study provides a systemic view of vancomycin's effects on HK-2 cells, highlighting potential therapeutic targets and biomarkers.
- Quantitative proteomics offers a promising approach for identifying novel biomarkers of drug-induced renal toxicity.
