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

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Funding

The present study was supported by Grants from the National Natural Science Foundation of China (Grant no. 81600540), Natural Science Foundation of Jiangsu Province (Grant no. BK20150224), Science and Technology Foundation of Xuzhou City (Grant no. KC16SL119), Jiangsu Entrepreneurial Innovation Program, Jiangsu Six Talent Peaks Project, Jiangsu Health International (regional) Exchange Support Program, and the Xuzhou Entrepreneurial Innovation Program.

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Authors

Contributions

LS and LZ conceived and designed the experiments. LS, LZ, YH, DZ, JW and TC performed the experiments. LS and LZ analyzed the data. YH and DZ contributed reagents/materials/analysis tools. LS wrote the paper, and LS and LZ revised the manuscript.

Corresponding authors

Correspondence to Ling Sun or Lu-Xi Zou.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The present study was approved by the Biomedical Research Ethics Committee of Xuzhou Central Hospital, College of Southeast University (Jiangsu, China).

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Sun, L., Zou, LX., Han, YC. et al. Role of A20/TNFAIP3 deficiency in lupus nephritis in MRL/lpr mice. Clin Exp Nephrol 24, 107–118 (2020). https://doi.org/10.1007/s10157-019-01826-2

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  • DOI: https://doi.org/10.1007/s10157-019-01826-2

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