Complement might be the Link between Diabetic Kidney Disease and Immunology: Identification of the Shared Gene Signatures and Molecular Mechanism in Diabetic Kidney Disease and Immune-Related Kidney Diseases

Abstract

AbstractBackground Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM), which is the main cause of end-stage renal disease and renal replacement therapy. In recent years, more and more studies have described the immune-related mechanisms of kidney injury such as inflammation. But anti-inflammatory therapies are difficult to gain effect. Methods To explore immune-related mechanisms of DKD, we compared it with immune-related kidney diseases using bioinformatics analysis. We searched for DKD and membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN) and anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) in Gene Expression Omnibus (GEO) database. We downloaded RNA sequences and patient information for these five kidney diseases. We used Metascape software to analyze the enrichment of differentially expressed genes (DEGs) and shared genes in these diseases. By drawing the protein-protein interaction (PPI) network map, we screened out the hub genes, and used receiver operating characteristics (ROC) curve to perform diagnostic tests. Results We found that DKD shares 66 pathways with MN, 9 pathways with IgAN, 85 pathways with LN, and 54 pathways with AAV. Among them, the number of up-regulated pathways shared in the glomeruli was the largest. These pathways were mainly immune related pathways such as inflammation. We further analyzed the shared genes between DKD and LN or AAV, and found that the hub genes were C1QA, C1QB, C1R and C1S. These genes are associated with complement activation. Moreover, compared with healthy controls, their abnormal expression levels have diagnostic significance for DKD. At last, we used a network meta-analysis to confirm that current anti-inflammatory therapy is difficult to effectively treat DKD. Conclusions This study suggests that although there may be an immunological cause of renal injury in DKD, complement activation plays the key role in the occurrence and development of DKD. This would provide potential targets for novel therapies of DKD.