Abstract
Lupus nephritis (LN) is associated with extensive injury and nephron loss in the afflicted kidney. Evidence has revealed the involvement of dysregulated Yin Yang 1 (YY1), a reported inflammatory modulator, in LN-induced kidney injury, and our microarray profile identified downregulated YY1 expression. Therefore, this study explored the functional relevance and mechanism of YY1 in LN-induced kidney injury. LN was modeled in mice by intraperitoneal injection of pristane, and Jurkat cells (CD41 human T lymphocytes) were activated with TNF-α to mimic the inflammatory environment found in LN. The expression patterns of YY1 and bioinformatics predictions of the downstream factor IFN-γ were confirmed in renal tissues from the mice with LN using qRT-PCR and Western blot analyses. The contents of proinflammatory cytokines in mouse serum samples and cell supernatants were determined using enzyme-linked immunosorbent assays (ELISAs). Ectopic expression and depletion approaches were subsequently used in vitro and in vivo to examine the effects of the YY1/IFN-γ/Fra2/PARP-1/FOXO1 axis on TNF-α-induced inflammation and LN-induced kidney injury. The results showed downregulated expression of YY1 and FOXO1 in the kidney tissues of the mice with LN. Increased proinflammatory factor production was observed in the mice with LN and TNF-α-treated Jurkat cell supernatant, accompanied by increased cell apoptosis and a high ratio of Th17/Treg cells, and these effects were reversed by YY1 restoration. YY1 was further shown to inhibit IFN-γ expression and thereby downregulate Fra2 expression. Fra2 depletion then inhibited PARP-1 expression and promoted FOXO1 expression to suppress cell apoptosis and the release of inflammatory factors. Collectively, our findings revealed that YY1 may alleviate LN-induced renal injury via the IFN-γ/Fra2/PARP-1/FOXO1 axis.