Integrative bioinformatics and experimental analysis reveals FRA1 as a key mediator of tubulointerstitial inflammation in lupus nephritis.

Tubulointerstitial injury is a key driver of lupus nephritis (LN) progression, and dysregulation of the immune microenvironment is a central feature of this process. The molecular mediators of this dysregulation remain incompletely defined. In the present study an integrated bioinformatics and experimental analysis was performed of the Activator Protein 1 (AP‑1) family transcription factor Fos‑related antigen 1 (FRA1) in LN tubulointerstitium. Analysis of gene expression omnibus datasets (GSE113342, GSE200306 and GSE127797) showed that FRA1 was markedly upregulated in the tubulointerstitium of LN samples and that its expression positively correlated with CD8(+) T cells, regulatory T cells, monocytes, M1 macrophages and activated mast cells, but negatively correlated with plasma cells, resting CD4(+) memory T cells, M0/M2 macrophages, resting dendritic cells and resting mast cells. In vivo experiments revealed that, FRA1 expression was also increased in kidneys from MRL/lpr mice. Furthermore, in vitro, lentiviral overexpression of FRA1 in HK‑2 cells induced robust upregulation of IL‑6, IL‑1β, IL‑8, MCP‑1 and RANTES, whereas FRA1 knockdown selectively decreased IL‑6 and RANTES levels. Together, these results indicate that FRA1 is significantly elevated in the LN tubulointerstitium and may foster a proinflammatory microenvironment by regulating key cytokines. The FRA1/AP‑1 axis therefore represents a potential regulator of renal inflammation in LN and a candidate therapeutic target.