SLC7A11 is upregulated during LPS-induced peritoneal inflammation and is negatively regulated by PPARγ

Peritonitis is a major complication of peritoneal dialysis and is closely associated with inflammatory injury of peritoneal mesothelial cells (PMCs). Solute carrier family 7 member 11 (SLC7A11), a key component of the cystine/glutamate antiporter system x c − , has been implicated in inflammatory regulation; however, its role in peritonitis remains unclear. In this study, we found that SLC7A11 expression was significantly upregulated in peritoneal tissues from a lipopolysaccharide (LPS)-induced mouse model of peritonitis and in LPS-stimulated PMCs. Knockdown of SLC7A11 attenuated LPS-induced inflammatory responses, as evidenced by decreased expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and cluster of differentiation 14 (CD14). In addition, SLC7A11 knockdown reduced LPS-induced phosphorylation of p65, a major subunit of nuclear factor-kappa B (NF-κB), suggesting that SLC7A11 may contribute to inflammatory activation, at least in part, through NF-κB signaling. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) analysis identified SLC7A11 as a potential downstream target of peroxisome proliferator-activated receptor gamma (PPARγ). ChIP-qPCR further confirmed that LPS reduced the binding of PPARγ to the SLC7A11 promoter. Moreover, activation of PPARγ by rosiglitazone suppressed SLC7A11 expression, whereas inhibition of PPARγ by GW9662 enhanced SLC7A11 expression. Collectively, these findings demonstrate that SLC7A11 contributes to LPS-induced peritoneal inflammation and is negatively regulated by PPARγ. The PPARγ–SLC7A11 axis may represent a potential regulatory mechanism and therapeutic target in peritonitis.