The occurrence of lupus nephritis is regulated by USP7-mediated JMJD3 stabilization

Ubiquitin-specific peptidases7 (USP7) participates in the regulation of various metabolic and immune disorders. However, the role of USP7 in lupus nephritis (LN) remains unknown. The current study set out to elucidate the regulatory role of USP7 in LN together with JMJD3 and NF-κB. SLE MRL/LPR mice and mouse glomerular mesangial cells SV40 MES 13 cells were employed for in vivo or vitro experiments. USP7, JMJD3 and NF-κB expression in MRL/LPR mice were detected, followed by investigation of their functions in the proliferation of mesangial cells and mesangial matrix. Subsequently, the interaction among USP7, JMJD3 and NF-κB was determined by means of ChIP and co-immunoprecipitation assay. The results indicated that USP7, JMJD3, p-NF-κB p65 were all highly-expressed in MRL/LPR mice. USP7 promoted the proliferation of mesangial cells and mesangial matrix, and stabilized the JMJD3 protein via deubiquitination in SV40 MES 13 cells. Meanwhile, silencing of JMJD3 inhibited the promotive effect of USP7 on the proliferation of mesangial cells and mesangial matrix. Furthermore, JMJD3 increased the expression of NF-κB p65 through demethylation, whereas silencing JMJD3 alleviated the proliferation of mesangial cells and mesangial matrix. Lastly, NF-κB p65 was proved to aggravate LN pathogenesis. Altogether, our findings highlighted that USP7 promoted the occurrence of LN by regulating the NF-κB p65 signaling pathway via stabilization of JMJD3.