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Updated: Jun 23, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics
Shucheng Si1,2, Hongyan Liu1,2, Lu Xu1,2
1Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, China.
Background:
Chronic kidney disease (CKD) is a progressive disease for which there is no effective cure. We aimed to identify potential drug targets for CKD and kidney function by integrating plasma proteome and transcriptome.
Methods:
We designed a comprehensive analysis pipeline involving two-sample Mendelian randomization (MR) (for proteins), summary-based MR (SMR) (for mRNA), and colocalization (for coding genes) to identify potential multi-omics biomarkers for CKD and combined the protein-protein interaction, Gene Ontology (GO), and single-cell annotation to explore the potential biological roles. The outcomes included CKD, extensive kidney function phenotypes, and different CKD clinical types (IgA nephropathy, chronic glomerulonephritis, chronic tubulointerstitial nephritis, membranous nephropathy, nephrotic syndrome, and diabetic nephropathy).
Results:
Leveraging pQTLs of 3032 proteins from 3 large-scale GWASs and corresponding blood- and tissue-specific eQTLs, we identified 32 proteins associated with CKD, which were validated across diverse CKD datasets, kidney function indicators, and clinical types. Notably, 12 proteins with prior MR support, including fibroblast growth factor 5 (FGF5), isopentenyl-diphosphate delta-isomerase 2 (IDI2), inhibin beta C chain (INHBC), butyrophilin subfamily 3 member A2 (BTN3A2), BTN3A3, uromodulin (UMOD), complement component 4A (C4a), C4b, centrosomal protein of 170 kDa (CEP170), serologically defined colon cancer antigen 8 (SDCCAG8), MHC class I polypeptide-related sequence B (MICB), and liver-expressed antimicrobial peptide 2 (LEAP2), were confirmed. To our knowledge, 20 novel causal proteins have not been previously reported. Five novel proteins, namely, GCKR (OR 1.17, 95% CI 1.10-1.24), IGFBP-5 (OR 0.43, 95% CI 0.29-0.62), sRAGE (OR 1.14, 95% CI 1.07-1.22), GNPTG (OR 0.90, 95% CI 0.86-0.95), and YOD1 (OR 1.39, 95% CI 1.18-1.64,) passed the MR, SMR, and colocalization analysis. The other 15 proteins were also candidate targets (GATM, AIF1L, DQA2, PFKFB2, NFATC1, activin AC, Apo A-IV, MFAP4, DJC10, C2CD2L, TCEA2, HLA-E, PLD3, AIF1, and GMPR1). These proteins interact with each other, and their coding genes were mainly enrichment in immunity-related pathways or presented specificity across tissues, kidney-related tissue cells, and kidney single cells.
Conclusions:
Our integrated analysis of plasma proteome and transcriptome data identifies 32 potential therapeutic targets for CKD, kidney function, and specific CKD clinical types, offering potential targets for the development of novel immunotherapies, combination therapies, or targeted interventions.
Insights
This study identified 32 proteins associated with chronic kidney disease (CKD) and kidney function by integrating proteome and transcriptome data. These findings offer potential new therapeutic targets for CKD and related conditions.
Area of Science:
- Genomics and Proteomics
- Nephrology
- Biomarker Discovery
Background:
- Chronic kidney disease (CKD) is a progressive condition with no effective cure.
- Identifying novel therapeutic targets is crucial for managing CKD and preserving kidney function.
Purpose of the Study:
- To identify potential drug targets for CKD and kidney function.
- To integrate plasma proteome and transcriptome data for multi-omics biomarker discovery.
Main Methods:
- Utilized two-sample Mendelian randomization (MR), summary-based MR (SMR), and colocalization analysis.
- Integrated protein-protein interaction, Gene Ontology (GO), and single-cell annotation to explore biological roles.
- Analyzed CKD, kidney function phenotypes, and various CKD clinical types.
Main Results:
- Identified 32 proteins associated with CKD, validated across datasets and clinical types.
- Confirmed 12 previously known proteins and identified 20 novel causal proteins.
- Five novel proteins (GCKR, IGFBP-5, sRAGE, GNPTG, YOD1) passed rigorous MR, SMR, and colocalization analyses.
Conclusions:
- The integrated analysis identified 32 potential therapeutic targets for CKD.
- These targets offer promise for developing novel immunotherapies, combination therapies, or targeted interventions for CKD.
