Proteomics-Based Identification of Potential Therapeutic Targets of Artesunate in a Lupus Nephritis MRL/lpr Mouse Model

• Published in: Journal of proteome research Vol. 23; no. 4; pp. 1150 - 1162
• Main Authors: Wen, Qiong, Wang, Cong, Chen, Dongni, Luo, Ning, Fan, Jinjin, Zhou, Yi, Yu, Xueqing, Chen, Wei
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.04.2024
• Subjects: Animals; antigen presentation; apoptosis; Artesunate - therapeutic use; autoantibodies; blood serum; cathepsin S; Cathepsins - therapeutic use; Female; females; fluorescent antibody technique; gene expression regulation; immunohistochemistry; Kidney - metabolism; Lupus Nephritis - drug therapy; Lupus Nephritis - pathology; mass spectrometry; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; nephritis; prediction; prednisone; proteinuria; Proteinuria - drug therapy; Proteinuria - metabolism; Proteinuria - pathology; proteome; Proteomics; Tandem Mass Spectrometry; therapeutics; lupus nephritis; artesunate; MRL/lpr mouse model; cathepsin S; quantitative proteomics
• ISSN: 1535-3893; 1535-3907; 1535-3907
• DOI: 10.1021/acs.jproteome.3c00558

This study aimed to identify potential therapeutic targets of artesunate in an MRL/lpr lupus nephritis mouse model by quantitative proteomics. We detected serum autoimmune markers and proteinuria in 40 female mice that were divided into 4 groups (n = 10): normal C57BL/6 control group; untreated MRL/lpr lupus; 9 mg/kg/day prednisone positive control MRL/lpr lupus; and 15 mg/kg/day artesunate-treated MRL/lpr lupus groups. Renal pathology in the untreated MRL/lpr lupus and artesunate groups was examined by Periodic acid-Schiff (PAS) staining. Artesunate treatment in lupus mice decreased serum autoantibody levels and proteinuria while alleviating lupus nephritis pathology. Through tandem mass tag-tandem mass spectrometry (TMT-MS/MS) analyses, differentially expressed proteins were identified in the artesunate group, and subsequent functional prediction suggested associations with antigen presentation, apoptosis, and immune regulation. Data are available via ProteomeXchange with the identifier PXD046815. Parallel reaction monitoring (PRM) analysis of the top 19 selected proteins confirmed the TMT-MS/MS results. Immunohistochemistry, immunofluorescence, and Western blotting of an enriched protein from PRM analysis, cathepsin S, linked to antigen presentation, highlighted its upregulation in the untreated MRL/lpr lupus group and downregulation following artesunate treatment. This study suggests that artesunate holds potential as a therapeutic agent for lupus nephritis, with cathepsin S identified as a potential target.