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Identification of Differentially Expressed Genes and Pathways in Non-Diabetic CKD and Diabetic CKD by Integrated
Clara Barrios1,2,3, Marta Riera2,3, Eva Rodríguez1,2,3
1Department of Nephrology, Hospital del Mar, 08003 Barcelona, Spain.
Insights
Diabetic chronic kidney disease (CKD_T2D) shows distinct molecular changes compared to non-diabetic CKD. Understanding these differences in gene expression is key for developing targeted treatments for kidney disease subtypes.
Area of Science:
- Nephrology
- Genomics
- Molecular Biology
Background:
- Chronic kidney disease (CKD) is a complex condition with diverse causes, including type 2 diabetes (T2D), hypertension, and autoimmune diseases.
- While diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share clinical signs, their underlying molecular mechanisms and distinctions remain unclear.
- Identifying specific molecular signatures is crucial for differentiating between diabetic and non-diabetic forms of CKD.
Purpose of the Study:
- To identify differentially expressed genes (DEGs) and enriched biological pathways in CKD_T2D versus CKD_nonT2D cohorts.
- To compare molecular profiles of CKD_T2D with autoimmune (CKD_nonT2D_AI) and hypertensive (CKD_nonT2D_HT) subtypes.
- To elucidate the transcriptomic landscape differentiating diabetic and non-diabetic kidney disease.
Main Methods:
- Integrative transcriptomic analysis of publicly available gene expression datasets from human kidney tissues (glomerular and tubulointerstitial).
- Utilized data from Gene Expression Omnibus (GEO) and ArrayExpress.
- Performed differential gene expression analysis and Gene Set Enrichment Analysis (GSEA).
Main Results:
- Significant overlap in DEGs between CKD_T2D and CKD_nonT2D, with CKD_T2D showing more pronounced gene expression alterations.
- Hypertensive CKD exhibited greater transcriptomic similarity to CKD_T2D than autoimmune CKD.
- Key DEGs related to fibrosis, inflammation, and complement activation (e.g., Tgfb1, Timp1, Cxcl6, C1qa/B) were altered in diabetic samples.
- GSEA indicated immune pathway enrichment in glomeruli and metabolic pathway enrichment in tubulointerstitium for CKD_T2D.
Conclusions:
- The transcriptomic profile of CKD_T2D demonstrates more significant immune and metabolic dysregulation compared to non-diabetic CKD.
- Distinct molecular mechanisms underlie diabetic versus non-diabetic forms of CKD.
- Findings support the development of tailored therapeutic strategies for specific CKD subtypes.
Abstract:
Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing diabetic from non-diabetic forms remain poorly defined. To identify differentially expressed genes (DEGs) and enriched biological pathways between CKD_T2D and CKD_nonT2D cohorts, including autoimmune (CKD_nonT2D_AI) and hypertensive (CKD_nonT2D_HT) subtypes, through integrative transcriptomic analysis. Publicly available gene expression datasets from human glomerular and tubulointerstitial kidney tissues were curated and analyzed from GEO and ArrayExpress. Differential expression analysis and Gene Set Enrichment Analysis (GSEA) were conducted to assess cohort-specific molecular signatures. A considerable overlap in DEGs was observed between CKD_T2D and CKD_nonT2D, with CKD_T2D exhibiting more extensive gene expression changes. Hypertensive-CKD shared greater transcriptomic similarity with CKD_T2D than autoimmune-CKD. Key DEGs involved in fibrosis, inflammation, and complement activation-including Tgfb1, Timp1, Cxcl6, and C1qa/B-were differentially regulated in diabetic samples, where GSEA revealed immune pathway enrichment in glomeruli and metabolic pathway enrichment in tubulointerstitium. The transcriptomic landscape of CKD_T2D reveals stronger immune and metabolic dysregulation compared to non-diabetic CKD. These findings suggest divergent pathological mechanisms and support the need for tailored therapeutic approaches.
