Abstract
Aim:
Aberrantly glycosylated IgA1 is a key factor in the pathogenesis of IgA nephropathy (IgAN). In this study we investigated the effects of aggregated IgA1 derived from IgAN patients (P-aIgA1) on human renal mesangial cells (HMCs) and the anti-proliferative and antifibrotic effects of histone deacetylase (HDAC) inhibitors in vitro.
Methods:
Three types of IgA1 were prepared, ie, N-IgA1 (IgA1 from healthy volunteers), P-IgA1 (IgA1 from IgAN patients), and P-aIgA1 (aggregated IgA1 from IgAN patients). The isolated IgA1 was heated for thermal polymerization. The proliferation of human renal mesangial cells (HMCs) were assessed using MTT assay. The expression levels of relevant proteins were examined using immunoblotting assays or immunohistochemistry.
Results:
P-aIgA1 (25–250 μg/mL) dose-dependently promoted the proliferation of HMCs, and markedly increased the protein levels of type I histone deacetylase (HDAC1, HDAC2 and HDAC8) in the cells. Both P-IgA1 and N-IgA1 were much weaker in stimulating cell proliferation and HDAC expression. P-aIgA1 (50 μg/mL) markedly increased the protein levels of Col1a1 and PAI-1, as well as pSmad2/3 and pStat3 in the cells. Pretreatment with the HDAC inhibitor trichostatin A (TSA, 250 nmol/L) or valproic acid (VPA, 400 μg/mL) partially reversed P-aIgA1-induced cell proliferation and extracellular matrix synthesis in HMCs.
Conclusion:
P-aIgA1 produces pro-proliferative and profibrotic actions in HMCs via upregulating the expression of HDACs, and subsequently activating TGF-β/Smad2/3 and Jak2/Stat3 signaling pathways. Both VPA and TSA attenuate P-aIgA1-induced cell proliferation and fibrosis in HMCs.
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Acknowledgements
This work was supported, in part, by the National Natural Science Foundation of China (81270782 and 30771000), the Key Projects of National Basic Research Program of China (973 Program; 2012CB517701 and 2012CB517604), the National Key Technology R&D Program (2011BAI10B00 and 2011BAI10B06). Key discipline construction projects have been approved by Health Development Planning Commission of Shanghai, National Project for the Construction of Clinical Key Specialty, Project of Special Fund For Health-Scientific Research (201002010), “New Talent in Xinglin” Training Project of Shanghai (ZYSNXD011-RC-XLXX-20130003).
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Dai, Q., Liu, J., Du, Yl. et al. Histone deacetylase inhibitors attenuate P-aIgA1-induced cell proliferation and extracellular matrix synthesis in human renal mesangial cells in vitro. Acta Pharmacol Sin 37, 228–234 (2016). https://doi.org/10.1038/aps.2015.79
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DOI: https://doi.org/10.1038/aps.2015.79
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