Combined transcriptomics and proteomics analysis reveals mechanisms underlying refractory lupus nephritis in children

Lupus nephritis (LN) is a major cause of morbidity among patients with systemic lupus erythematosus (SLE). Unfortunately, some patients do not respond adequately to available therapies, and the gene expression changes underlying this refractory state are still poorly understood. Therefore, it is crucial to gain a better understanding of the molecular mechanisms involved in refractory LN.

Integrated proteomic and transcriptomic analysis was conducted to characterize the unique gene expression profiles in patients with refractory LN. DEGs/DAPs were identified based on the concordance between transcriptome and proteome data. Subsequently, functional enrichment analyses and protein-protein interaction network analyses were performed. Module analysis was carried out using the Search Tool for the Retrieval of Interacting Genes and Cytoscape software. Additionally, the clinical features of these patients were explored. To identify potential therapeutic agents, the Connectivity Map L1000 platform was employed.

Seventeen patients were included in the study, 12 non-refractory LN and 5 refractory LN. There was no statistically significant difference in demographic data, clinical characteristics and laboratory findings. There were 1019 DAPs in non-refractory LN compared with refractory LN and 47 DEGs totally in glomeruli and tubulointerstitium from GSE200306 dataset between two groups. Finally, we obtained 7 DEGs/DAPs, including CD59, JAK1, VCAM1, C8A, PIGR, TGFBI and VTN. The functions and pathways associated with the DEGs/DAPs mainly associated with complement and coagulation cascades. We also found that T cells CD4 memory (activated) downregulated in refractory LN. In both proteomics and transcriptomics analysis, CD59 was downregulated in refractory LN. And CD59 positively correlated with Alb and negatively correlated with CH50. In addition, we discovered several chemicals as potential treatment options for refractory LN.

According to our research findings, we have discovered that abnormal activation and functional defects of the complement system play a significant role in refractory lupus nephritis. In particular, the decreased expression of CD59 indicates abnormal complement activation. Therefore, inhibiting complement activation may become a new strategy for treating refractory LN. Key Points • The first explore of specific gene expression changes associated with refractory LN combined transcriptomics and proteomics analysis. • The functions and pathways associated with the DEGs/DAPs mainly associated with complement and coagulation cascades. • CD59 was downregulated in refractory LN. CD59 positively correlated with Alb and negatively correlated with CH50.