#4477 identification of differentially expressed genes and pathways in non-diabetic ckd and diabetic ckd by integrated bioinformatics analysis

Abstract Background and Aims Chronic kidney disease (CKD) is a complex genetic-based disease with multiple unclarified molecular pathways involved. Dapagliflozin have shown a clear improvement in the progress of renal function and CV risk in both diabetic and non-diabetic populations. However, we do not really know the molecular pathways that this drug modulates. To overcome this global objective we have first seek similarities and differences in genes and molecular pathways implicated in Non-diabetic (Non-DM) CKD (considering Autoimmune-CKD and Hypertension-CKD) and type2 diabetic nephropathy (DN). Method Expression datasets were compiled from databases (ArrayExpress and Gene Expression Omnibus). Differential expression analysis (DEA) and Gene Set Enrichment Analysis (GSEA) were carried out; each cohort was compared with controls, and between them as direct comparison (Non-DM CKD vs. DN). Results Non-DM CKD and DN share many similarities when compared to controls. However, some quantitative differences come up in terms of genes and pathways (see Figure 1 for examples). (1) Hypertension-CKD is clearly closer to DN than Autoimmune-CKD in both glomeruli and tubulointerstitium both in gene and pathway analysis. (2) Extracellular matrix remodelling and immune system activation (innate and adaptive) are processes involved in Non-DM CKD and DN but show a higher activation in DN. (3) Metabolic modulations, regarding metabolic acidosis, reprograming and dyslipidaemia, are more present in DN tubulointerstitium than Non-DM CKD subcohorts, tubulointerstitium specifically. (4) Genes related to complement activation are found overexpressed in DN glomeruli compared to CKD/subcohorts, which then translate to a complement system activation rise in the GSEA analysis. Conclusion We raise a series of core genes that may be potential targets for the study of Dapagliflozin mechanism of action.