SHP2 inhibitor mitigated renal tubular epithelial cell injury in lupus nephritis via ERK/NF-κB pathway.

Objectives: The Src homology phosphatase 2 (SHP2) has been shown to be associated with systemic lupus erythematosus (SLE). However, its role and specific mechanisms in lupus nephritis (LN) remains unknown. In this study, we aimed to explore the efficacy and mechanism of targeting SHP2 for treatment of LN.

Methods: The SHP2 was detected in renal tissues of MRL/lpr mice by western blot and immunohistochemistry. The MRL/lpr mice were divided into control group, PBS group and treatment group. The treatment group received SHP099 (SHP2 inhibitor) intraperitoneally daily for 4 weeks. The lupus-like symptoms and renal histopathological changes of mice in the PBS and SHP099 groups were evaluated. The expression of inflammation and fibrosis-related genes in renal tissues was detected by RT-qPCR. The renal tubular epithelial cell (HK-2) injury was induced by lipopolysaccharide (LPS). The effects of SHP099 and ERK/NF-κB signalling pathway on LPS-treated-HK-2 cells were assessed.

Results: SHP2 was activated in kidney tissues of MRL/lpr mice. After treatment with SHP099, renal pathology was alleviated, inflammation- and fibrosis-related gene expression levels were reduced, and ERK/NF-κB signalling pathway-related protein was reduced in MRL/lpr mice. SHP099 inhibited LPS-induced inflammatory activation in HK-2 cells. SHP099 regulated ERK/NF-κB signalling pathway in HK-2 cells.

Conclusions: Our findings suggested that inhibition of SHP2 mitigated renal tubular epithelial cell injury in LN through regulating the ERK/NF-κB signalling pathway. Our study elucidated the mechanism of the beneficial effects of SHP2 inhibitor on LN and provided a promising therapeutic strategy to treat LN.