title: Histone deacetylase inhibitors attenuate P-aIgA1-induced cell proliferation and extracellular matrix synthesis in human renal mesangial cells in vitro.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.|Department of Nephrology, the Central Hospital of Xuhui District, Shanghai 200031, China.|Department of Nephrology, Punan Hospital, Shanghai 200125, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Yun-lei
authors.initials: YL
authors.lastname: Du
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Ying
authors.affiliation: Shanghai Institute of Hematology, Shanghai 200025, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Nephrology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China.
authors.forename: Li-qun
authors.initials: LQ
authors.lastname: He
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei-ming
authors.initials: WM
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007070:Immunoglobulin A / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007070:Immunoglobulin A; C012589:trichostatin A; D014635:Valproic Acid