Aims/Introduction

It is not unclear whether the complement system is involved in the pathogenesis of diabetic nephropathy (DN). We explored the role of the complement system in glomeruli from patients with DN using integrated transcriptomic bioinformatics analysis and renal histopathology.

Materials and Methods

Four datasets (GSE30528, GSE104948, GSE96804 and GSE99339) from the Gene Expression Omnibus database were integrated. We used a protein-protein interaction network and the Molecular Complex Detection app to obtain hub genes. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to identify significant pathways. We also investigated the associations of C1q and C3 deposition on renal histopathology with clinical data, pathological parameters, and renal survival in DN patients.

Results

We identified 47 up- and 48 downregulated genes associated with DN. C3, C1QB, and C1QA were found to be complement-related hub genes. The GO and KEGG analyses identified complement activation and humoral immune response as the significant oncology terms, with C1QB and C3 positioned at the center of the pathway. Regarding renal histopathology, the patients had more severe glomerular classes. Multivariate Cox proportional hazards regression revealed that the deposition of glomerular C1q and C3 was an independent risk factor for kidney failure. Patients with high C1q, C3, or C4d expression in glomeruli were more likely to progress to kidney failure, whereas glomerular mannose-binding lectin was rare.

Conclusions

Complement activation is involved in the development of DN, and activation of the classical complement pathway in glomeruli may accelerate disease progression.