Intraglomerular synthesis of complement C3 and its activation products in IgA nephropathy

Background: Complement activation is thought to be pathologically important in IgA nephropathy (IgAN). Although C3 deposition in the mesangium is foun d in IgAN, the origin of C3 is not clear. We recently demonstrated intraglo merular C3 synthesis in the human kidney; however, the activation and patho logical role of locally synthesized C3 remains unclear. Here we performed n onradioactive in situ hybridization for C3 mRNA and immunohistochemistry fo r C3 and its activation products, such as C3d and membrane attack complex ( MAC), to determine whether locally produced C3 in glomeruli was activated i n IgA nephropathy. Methods: Renal samples from 14 patients with IgAN and 5 with minimal change nephrotic syndrome (MCNS) were examined. Uninvolved por tions of surgically removed kidneys with tumors served as normal controls. Results: C3 mRNA was not detected in glomeruli in control tissue and MCNS, but was strongly expressed in resident glomerular cells of IgAN, including mesangial cells, glomerular epithelial cells and the cells of Bowman's caps ule. Examination of serial sections disclosed that more than 70% of cells p ositive for C3 mRNA were also stained for C3 protein, C3d, and MAC. Double staining for in situ hybridization and immunohistochemistry also revealed t hat those C3 mRNA signals were present in intraglomerular cells positive fo r C3. The expression of C3 mRNA and MAC in glomeruli correlated significant ly with the degree of mesangial matrix expansion. Conclusions: Our results demonstrated that locally synthesized C3 is activated in the glomeruli of I gAN and that its expression correlated with the severity of mesangial matri x expansion. These findings suggest that activation of C3 may be involved i n tissue injury in IgAN th rough the formation of membrane attack complex. Copyright (C) 2001 S. Karger AG, Basel.