A Systems Approach Identifies The Holistic Map of Diabetic Nephropathy

Background: Chronic diseases are the main cause of death and disability in human society. Despite different investigations, the molecular mechanisms are not fully discovered. Systems biol-ogy approaches can enhance our knowledge about these com-plex diseases. Diabetic nephropathy (DN), as a chronic disease, is one of the major complications of diabetes mellitus patients. In spite of huge investigations, a holistic view of this complex disorder has rarely been done. In this study, we have reanalyzed a microarray dataset of the kidney cortex of diabetes mice, to identify key genes and functions in this complex condition.Materials and Methods: A microarray datasets GSE86300 (kidney cortex) which is the expression profile of db/db mice and healthy individuals were downloaded from Gene Expres-sion Omnibus (GEO) database. The quality of each dataset was evaluated by unsupervised hieratical clustering and princaple component analysis (PCA) by GGplot2 package of R software. Using GEO2R and considering adjusted P-value<0.05, differ-entially expressed (DE) genes were identified. Next, transcrip-tion factors (TF) regulating DE genes and kinases controlling TFs by with P-value≤0.05 harvested using EnrichR database. After that, using CluePedia application of Cytoscape software version 3.5.1, the multilayer networks of DE genes, TFs, and kinase were constructed. NetworkAnalyser tool of Cytoscape was used for network analyses. In continue, pathways and gene ontology (GO) terms were collected using ClueGo application of Cytoscape.Results: The quality of dataset was acceptable as PCA separat-ed disease and normal samples. 1042 DE genes, 35 TFs, and 41 kinases was harvested, in this dataset. Among central DE genes, that revealed by network’s topology analysis, Wt1, Mapk fam-ily, and Sox2 was observed which have been previously con-firmed in the pathogenesis of DN. Also, some new genes like Suz12 and Rxra were introduced for the first time. Pathway enrichment analysis identified some well-known role player in DN such as FoxO and ErbB signalling pathway, and likewise MAPK signalling cascade. Enriching Neurotrophin signalling pathway was in line with our previous unpublished data on DN and validated in this one. In addition, small molecule metabo-lism, lipid metabolic process, and anion binding were among GO-term enrichment analysis.Conclusion: In conclusion, here we have shown the central genes, key signalling pathways and GO-terms in DN. These findings deepen our knowledge about the pathogenesis of this complex disease.

کلیدواژه ها:

Diabetic Nephropathy ، Differential Expressed Gene ، Microarray Analysis ، Pathway Enrichment Analysis