Role of A20/TNFAIP3 deficiency in lupus nephritis in MRL/lpr mice.

Abstract

The activation of the nuclear factor-κB (NF-κB) signaling pathway gives rise to inflammation in the pathogenesis of lupus nephritis (LN), with A20 serving as a negative feedback regulator and ubiquitin C‑terminal hydrolase L1 (UCH-L1) acting as a downstream target protein. However, their roles in the mechanism of LN remain undetermined. In the present study, the expression of A20 and UCH-L1, the activity of NF-κB and ubiquitin-proteasome system (UPS) were measured in MRL/lpr mice and A20 gene silenced podocytes. The severity of podocyte injury and immune complex deposits were detected by transmission electron microscopy. The in vivo experiments revealed that A20 failed to terminate the activation of NF-κB, which was accompanied by UCH-L1 overexpression, ubiquitin accumulation, and glomerular injury in LN mice. Immunosuppression therapy did improve LN progression by attenuating A20 deficiency. In vitro experiments confirmed that tumor necrosis factor-α induced NF-κB activation, which led to UCH-L1 overexpression, UPS impairment, the upregulation of desmin and the downregulation of synaptopodin in A20 gene silenced podocytes. Thus, the results of the present study suggest that A20 regulates UCH-L1 expression via the NF-κB signaling pathway and A20 deficiency might play an important role in LN pathogenesis. Therefore, the A20 protein may serve as a promising therapeutic target for LN.