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Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Proteomic Characterization of Replication Stress and Impaired Antioxidant Defense in Tacrolimus-Induced Chronic
Tamaki Ishima1, Sho Nishida1,2, Shota Tomida1
1Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan.
Abstract:
Tacrolimus (TAC) nephropathy is a major complication of immunosuppressive therapy and contributes to chronic kidney disease (CKD) progression through ischemia, metabolic dysfunction, and oxidative stress; however, its protein-level basis remains unclear. This study sought to identify characteristic molecular alterations in renal cortices of TAC-treated mice, so as to clarify the link between replication stress responses and metabolic dysfunction. A previously generated proteomic dataset from a TAC-induced chronic nephrotoxicity mouse model was analyzed using a protein-centered analytical strategy, including statistical, Gene Ontology, pathway, upstream regulator, and disease-enrichment analyses. A total of 7466 proteins were quantified. Upregulated proteins included KAT6A and NCKAP1, whereas downregulated proteins included NDUFC2, HSD17B12, and TECR. Coordinated impairment of CoQ10-dependent and glutathione-dependent antioxidant defenses was identified, reflected by reductions in AIFM2 (FSP1) and GSTA4/GSTT2. Enrichment analyses indicated activation of MCM- and ATR-associated replication stress responses in the upregulated group, and impaired lipid metabolism, CoA biosynthesis, mitochondrial function, and redox regulation in the downregulated group. TAC nephropathy is characterized by two major molecular signatures: central disruption of antioxidant defense systems, spanning FSP1-mediated CoQ10 regeneration and GST- associated antioxidant systems, together with suppression of lipid and energy metabolism and activation of replication stress responses. These findings provide a protein-level molecular framework linking coordinated impairment of antioxidant defense systems, suppression of lipid and energy metabolism, and activation of replication stress responses in TAC-induced chronic nephrotoxicity. These findings also suggest the FSP1 pathway, GST-associated antioxidant systems, and CoA-dependent metabolism as potential therapeutic targets for CKD progression.
Insights
Tacrolimus (TAC) nephropathy disrupts kidney antioxidant defenses and metabolism, activating replication stress responses. This study reveals molecular links, suggesting new therapeutic targets for chronic kidney disease (CKD) progression.
Area of Science:
- Nephrology
- Proteomics
- Molecular Biology
Background:
- Tacrolimus (TAC) nephropathy is a significant complication of immunosuppressive therapy, contributing to chronic kidney disease (CKD) progression.
- The precise protein-level mechanisms underlying TAC nephrotoxicity, particularly the link between replication stress and metabolic dysfunction, remain incompletely understood.
Purpose of the Study:
- To identify characteristic molecular alterations in the renal cortex of TAC-treated mice.
- To elucidate the connection between replication stress responses and metabolic dysfunction in TAC nephropathy at the protein level.
Main Methods:
- Analysis of a previously generated proteomic dataset from a TAC-induced chronic nephrotoxicity mouse model.
- Application of a protein-centered analytical strategy, including statistical, Gene Ontology, pathway, upstream regulator, and disease-enrichment analyses.
- Quantification of 7466 proteins.
Main Results:
- Identified upregulated proteins (e.g., KAT6A, NCKAP1) and downregulated proteins (e.g., NDUFC2, HSD17B12, TECR).
- Revealed coordinated impairment of CoQ10-dependent and glutathione-dependent antioxidant defenses (reduced AIFM2/FSP1, GSTA4/GSTT2).
- Detected activation of MCM- and ATR-associated replication stress responses and impaired lipid metabolism, CoA biosynthesis, mitochondrial function, and redox regulation.
Conclusions:
- TAC nephropathy exhibits distinct molecular signatures: disrupted antioxidant defenses (FSP1, GST systems) and suppressed lipid/energy metabolism alongside activated replication stress responses.
- Established a protein-level framework linking impaired antioxidant defenses, suppressed metabolism, and replication stress in TAC-induced nephrotoxicity.
- Highlighted the FSP1 pathway, GST systems, and CoA-dependent metabolism as potential therapeutic targets for mitigating CKD progression.
