Histone deacetylase inhibitors attenuate P-algA1- induced cell proliferation and extracellular matrix synthesis in human renal mesangial cells in vitro  

作　　者：Qin DAI Jian LIU Yun-lei DU Xu HAO Ji YING Yun TAN Li-qun HE Wei-ming WANG Nan CHEN 

机构地区：[1]Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China [2]Department of Nephrology, the Central Hospital of Xuhui District, Shanghai 200031, China [3]Department of Nephrology, Punan Hospital, Shanghai 200125, China [4]Shanghai Institute of Hematology, Shanghai 200025, China [5]Department of Nephrology, Shuguang Hospital, Shang- hai University of Traditional Chinese Medicine, Shanghai 200021, China

出　　处：《Acta Pharmacologica Sinica》2016年第2期228-234,共7页中国药理学报（英文版）

摘　　要：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-algA1） 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-algA1 （aggregated IgAlfrom 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-algA1 （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-algA1 （50 pg/mL） markedly increased the protein levels of Collal 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 pg/mL） partially reversed P-algAl-induced cell proliferation and extracellular matrix synthesis in HMCs. Conclusion： P-algA1 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-algAl-induced cell proliferation and fibrosis in HMCs.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-algA1） 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-algA1 （aggregated IgAlfrom 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-algA1 （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-algA1 （50 pg/mL） markedly increased the protein levels of Collal 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 pg/mL） partially reversed P-algAl-induced cell proliferation and extracellular matrix synthesis in HMCs. Conclusion： P-algA1 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-algAl-induced cell proliferation and fibrosis in HMCs.

关 键 词：IgA nephropathy human renal mesangial cells HDAC trichostatin A valproic acid extracellular matrix synthesis SMAD2/3 STAT3 antifibrosis 

分 类 号：R9[医药卫生—药学]