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.
References
Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365:2110–211.
Jiang T, Tian F, Zheng HT, Whitman SA, Lin YF, Zhang ZG, et al. Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-kappa B-mediated inflammatory response. Kidney Int. 2014;85(2):333–43. https://doi.org/10.1038/ki.2013.343.
Ghosh S, Hayden MS. Celebrating 25 years of NF-kappa B research. Immunol Rev. 2012;246:5–13. https://doi.org/10.1111/j.1600-065X.2012.01111.x.
Hochstrasser M. Origin and function of ubiquitin-like proteins. Nature. 2009;458(7237):422–9. https://doi.org/10.1038/nature07958.
Sun L, Chen H, Hu C, Wang P, Li Y, Xie J, et al. Identify biomarkers of neuropsychiatric systemic lupus erythematosus by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry combined with weak cation magnetic beads. J Rheumatol. 2011;38(3):454–61.
Elouaai F, Lule J, Benoist H, Appolinairepilipenko S, Atanassov C, Muller S, et al. Autoimmunity to histones, ubiquitin, and ubiquitinated histone H2A in NZB × NZW and MRL-LPR/LPR mice—antihistone antibodies are concentrated in glomerular eluates of lupus mice. Nephrol Dial Transpl. 1994;9(4):362–6.
Parvatiyar K, Harhaj EW. Regulation of inflammatory and antiviral signaling by A20. Microbes Infect. 2011;13(3):209–15.
Musone SL, Taylor KE, Nititham J, Chu C, Poon A, Liao W, et al. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. Genes Immun. 2011;12(3):176–82.
Liu Y, Wu J, Wu H, Wang T, Gan H, Zhang X, et al. UCH-L1 expression of podocytes in diseased glomeruli and in vitro. J Pathol. 2009;217:642–53.
Zhang H, Sun Y, Hu R, Luo W, Mao X, Zhao Z, et al. The regulation of the UCH-L1 gene by transcription factor NF-κB in podocytes. Cell Signal. 2013;25:1574–85.
Wang R, Zhang M, Zhou W, Ly PTT, Cai F, Song W. NF-κB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression. J Neurochem. 2011;116:1160–70.
Zhou L, Lu L-M. Isolation and culture of renal glomeruli from rats. Acta Physiol Sin. 2015;67(6):629–35.
Shankland SJ, Pippin JW, Reiser J, Mundel P. Podocytes in culture: past, present, and future. Kidney Int. 2007;72(1):26–36. https://doi.org/10.1038/sj.ki.5002291.
Tewari R, Nada R, Rayat CS, Boruah D, Dudeja P, Joshi K, et al. Correlation of proteinuria with podocyte foot process effacement in IgA nephropathy: an ultrastructural study. Ultrastruct Pathol. 2014;17(2):1–5.
Perry D, Sang A, Yin YM, Zheng YY, Morel L. Murine models of systemic lupus erythematosus. J Biomed Biotechnol. 2011. https://doi.org/10.1155/2011/271694.
Du Y, Sanam S, Kate K, Mohan C. Animal models of lupus and lupus nephritis. Curr Pharm Des. 2015;21:2320–49.
Merinoo R, Shibata T, Kossodo SD, Izui S. Differential effect of the autoimmune Yaa and Ipr genes on the acceleration of lupus-like syndrome in MRL/MpJ mice. Eur J Immunol. 1989;19:2131–7.
Kalergis AM, Iruretagoyena MI, Barrientos MJ, Lez PAG, Herrada AA, Leiva ED, et al. Modulation of nuclear factor-kB activity can influence the susceptibility to systemic lupus erythematosus. Immunol Lett. 2008;128:e306–e314314.
Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, et al. Failure to regulate TNF-induced NF-κB and Cell death responses in A20-deficient mice. Science. 2000;289(5488):2350–4.
Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008;40:1059–61.
Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet. 2008;40:1062–4.
Sakurai M, Ayukawa K, Setsuie R, Nishikawa K, Hara Y, Ohashi H, et al. Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J Cell Sci. 2006;119:162–71.
Meyer-Schwesinger C, Meyer TN, Sievert H, Hoxha E, Sachs M, Klupp E-M, et al. Ubiquitin C-terminal hydrolase-L1 activity induces polyubiquitin accumulation in podocytes and increases proteinuria in rat embranous nephropathy. Am J Pathol. 2011;178(5):2044–57.
Zhang H, Gao X, Sun Y, Hu R, Luo W, Zhao Z, et al. NF-κB upregulates ubiquitin C-terminal hydrolase 1 in diseased podocytes in glomerulonephritis. Mol Med Rep. 2015;12(2):2893–901.
Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012;74:299–32323.
Anders H-J, Fogo AB. Immunopathology of lupus nephritis. Semin Immunopathol. 2014;36:443–59.
Kraft SW, Schwartz MM, Korbet SM, Lewis EJ. Glomerular podocytopathy in patients with systemic lupus erythematosus. J Am Soc Nephrol. 2005;16:175–9.
Trivedi S, Zeier M, Reiser J. Role of podocytes in lupus nephritis. Nephrol Dial Transplant. 2009;24:3607–12.
Beeken M, Lindenmeyer MT, Blattner SM, Radón V, Oh J, Meyer TN, et al. Alterations in the ubiquitin proteasome system in persistent but not reversible proteinuric diseases. J Am Soc Nephrol. 2014;25:2511–25.
Hoshi S, Shu Y, Yoshida F, Inagaki T, Sonoda J, Watanabe T, et al. Podocyte injury promotes progressive nephropathy in Zucker diabetic fatty rats. Lab Invest. 2002;82(1):25–35.
Li JS, Chen X, Peng L, Wei SY, Zhao SL, Diao TT, et al. Angiopoietin-Like-4, a potential target of tacrolimus, predicts earlier podocyte injury in minimal change disease. PLoS ONE. 2015. https://doi.org/10.1371/journal.pone.0137049.
Bitzan M, Babayeva S, Vasudevan A, Goodyer P, Torban E. TNF alpha pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and beta 3 integrin activation. Pediatr Nephrol. 2012;27(12):2217–26. https://doi.org/10.1007/s00467-012-2163-3.
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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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.
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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