Frontiers in immunology · 2026
Proteomic insights into aprotinin's immunomodulatory effects in attenuating renal fibrosis in a unilateral ureteral obstruction model.
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Wang Xinyu, Shen Ying, Chen Danlei, Ding Lele, Ding Yuanlong, Gan Peilin, Long Qian, Song Lu, Li Yaling, Tian Xin, Zhang Jun, Xu Jian, Kakizoe Yutaka, Yang Shu, Luo Fucheng, Deng Qinyuan
Аннотация
BACKGROUND: Chronic kidney disease involves progressive fibrosis and immune dysregulation. Aprotinin, a broad-spectrum serine protease inhibitor, has shown dose-dependent renal effects, but its role in obstructive nephropathy is unclear.
METHODS: A unilateral ureteral obstruction (UUO) mouse model was used to assess aprotinin at 0.5 mg/day and 1 mg/day delivered via osmotic pumps for 7 days. Renal injury and fibrosis was evaluated by histology, serum markers, and expression of inflammation- and fibrosis-related genes. Mechanistic insights were obtained through LC-MS/MS proteomic profiling, functional enrichment analysis, and CIBERSORT-based immune deconvolution. Key proteins, signaling pathways, and immune cell infiltration were validated by Western blotting, immunohistochemistry, and flow cytometry.
RESULTS: Aprotinin at 1 mg/day significantly reduced tubular injury and interstitial fibrosis, whereas the 0.5 mg/day dose showed minimal benefit. The higher dose caused mild increases in serum creatinine and blood urea nitrogen. Proteomic analysis identified differentially expressed proteins enriched in immune regulatory pathways. Cathepsin S (CTSS), a protease involved in antigen presentation, was markedly decreased by aprotinin. CIBERSORT revealed reduced follicular helper T cells and partial restoration of naïve CD4+ T cells following treatment. These changes were further confirmed by flow cytometry. Western blotting and immunohistochemistry confirmed reduced CTSS and CD4 expression, along with decreased CD4+ T-cell infiltration and inhibition of ERK signaling.
CONCLUSIONS: Aprotinin attenuates renal fibrosis in UUO in a dose-dependent manner. Its effects are associated with suppression of CTSS, inhibition of ERK signaling, and modulation of CD4+ T-cell subsets, and reduced immune cell infiltration. These findings indicate that aprotinin attenuates renal fibrosis through immunomodulatory mechanisms and support further investigation of serine protease inhibitors in immune-mediated kidney injury.
METHODS: A unilateral ureteral obstruction (UUO) mouse model was used to assess aprotinin at 0.5 mg/day and 1 mg/day delivered via osmotic pumps for 7 days. Renal injury and fibrosis was evaluated by histology, serum markers, and expression of inflammation- and fibrosis-related genes. Mechanistic insights were obtained through LC-MS/MS proteomic profiling, functional enrichment analysis, and CIBERSORT-based immune deconvolution. Key proteins, signaling pathways, and immune cell infiltration were validated by Western blotting, immunohistochemistry, and flow cytometry.
RESULTS: Aprotinin at 1 mg/day significantly reduced tubular injury and interstitial fibrosis, whereas the 0.5 mg/day dose showed minimal benefit. The higher dose caused mild increases in serum creatinine and blood urea nitrogen. Proteomic analysis identified differentially expressed proteins enriched in immune regulatory pathways. Cathepsin S (CTSS), a protease involved in antigen presentation, was markedly decreased by aprotinin. CIBERSORT revealed reduced follicular helper T cells and partial restoration of naïve CD4+ T cells following treatment. These changes were further confirmed by flow cytometry. Western blotting and immunohistochemistry confirmed reduced CTSS and CD4 expression, along with decreased CD4+ T-cell infiltration and inhibition of ERK signaling.
CONCLUSIONS: Aprotinin attenuates renal fibrosis in UUO in a dose-dependent manner. Its effects are associated with suppression of CTSS, inhibition of ERK signaling, and modulation of CD4+ T-cell subsets, and reduced immune cell infiltration. These findings indicate that aprotinin attenuates renal fibrosis through immunomodulatory mechanisms and support further investigation of serine protease inhibitors in immune-mediated kidney injury.