Identification of NET formation and the renoprotective effect of degraded NETs in lupus nephritis

Abstract

To explore molecular biomarkers associated with the pathophysiology and therapy of lupus nephritis (LN), we conducted a joint analysis of transcriptomic data from 40 PBMCs (GSE81622) and 21 kidney samples (GSE112943) from the GEO database using bioinformatics. 976 and 2427 differentially expressed genes (DEGs) were identified in PBMCs and renal tissues. Seven and two functional modules closely related to LN were identified. Further enrichment analysis revealed that the neutrophil activation pathway was highly active in both PBMC and kidney. Subsequently, 16 core genes closely associated with LN were verified by PPI screening and qPCR. In vitro cell models and MRL/lpr mouse models confirmed that the abnormal expression of these core genes was closely linked to neutrophil extracellular traps (NETs) generated by neutrophil activation, while degradation of NETs led to down-regulation of core gene expression, thereby improving pathological symptoms of LN. Therefore, identification of SLE patients exhibiting abnormal expression patterns for these core genes may serve as a useful indicator for kidney involvement. Additionally, targeting neutrophils to modulate their activation levels and inhibit aberrant expression of these genes represents a potential therapeutic strategy for treating LN.