The Study On The Mechanism Of SOCS1/STAT1 Regulate Renal Inflammation In Mesangial Proliferative Glomerulonephritis Models

Objective:Glomerulonephritis(GN)is characterized by intraglomerular inflammation and is a major cause of end-stage renal disease(ESRD).Inflammation plays a crucial role in the progress of mesangial proliferative glomerulonephritis(MsGN).Many forms of GN,such as immunoglobulin A nephropathy(IgAN),lupus nephritis(LN),and postinfectious endocapillary proliferative GN,are characterized by mesangial hyperplasia due to increased glomerular mesangial cell replication.Mesangial cell proliferation is a significant event in the development of progressive glomerular injuries,but the mechanisms common to both these important pathological findings remain unresolved.The suppressor of cytokine signaling(SOCS)proteins which are inhibitors of cytokine signaling pathways unveiled an important mechanism for the negative regulation of the cytokine-induced JAK/STAT pathway.SOCS1 participates in renal fibrosis by downregulating J AK2/S TAT 1-mediated cytokine signaling in LN and Diabetic Nephropathy.This study examined whether SOCS1 can regulate renal inflammation in MsGN models.Methods:In Vivo:Habu GN was induced in 18-to 20-g male C57BL/6 mice by intravenous(i.v.)tail injections of the Habu snake toxin Trimeresurus flavoviridis.Meanwhile,10 mice(per treatment group)were treated with either the STAT1 inhibitor fludarabine or vehicle once every other day.Thy 1.1 GN was induced in 180-to 200-g male rats by a single i.v.tail injection of Thy 1.1 monoclonal antibody.The expression of SOCS1,MHC class Ⅱ,STAT1,inflammatory cells and cytokines were analyzed in Habu and Thy 1.1 GN modes.In Vitro:IFN-y-stimulated mouse mesangial cells(MMCs)were transfected with SOCS1 plasmids.Meanwhile,we used STAT1 inhibitor fludarabine in IFN-γ treated MMCs.The expression of MHC class Ⅱ,STAT1 and cytokines were analyzed.Results:The number of macrophages and CD4+ T cells increased significantly in glomeruli of MsGN models.Expression of IFN-γ,TNF-α,IL-12A and IL-12B increased significantly in the course of Thy 1.1 and Habu nephritis.MHC class Ⅱ is expressed in mesangial cells of MsGN models.SOCS1 protein also showed a significant decrease and P-STAT1 increased significantly at early stage in MsGN models.STAT1 inhibitor decreases renal inflammation and ameliorates glomerular lesions in Habu GN.The overexpression of SOCS1 repress MHC class Ⅱ and STAT1 phosphorylation which is induced by IFN-γ in mesangial cells.STAT-1 inhibitor could inhibit IFN-γ-induced CIITA promoter activity and MHC class Ⅱ significantly.Conclusions:This study emphasizes the pivotal role of the SOCS1/STAT1 axis in regulating inflammation in mesangial proliferative glomerulonephritis.Mesangial cells have been identified as non-professional APCs in mesangial proliferative glomerulonephritis.In addition,it demonstrates that SOCS1 is a critical regulator of cellular sensitivity to IFN-γ-induced CIITA and MHC class Ⅱ expression in mesangial cells.The negative feedback between SOCS1/STAT1 expression and inflammation may play an important role in MsGN.