Up-regulated TGF-beta mRNA expression in splenic T cells of high IgA-pronemice: A murine model of IgA nephropathy with glomerulosclerosis

Background/Aims: Recently, we established a high serum IgA-prone inbred (HI GA) mouse strain as a murine model of spontaneous IgA nephropathy by select ive mating of high serum IgA ddY mice, and found that they showed enhanced production of glomerular extracellular matrix components with increased exp ression of TGF-beta mRNA and protein in the kidneys. In this study, we exam ined the roles of lymphocytes in the development of high serum IgA in this strain. Methods: We performed flow cytometric analyses of T and B cells in splenic mononuclear cells (SMNCs) from these mice using BALB/c mice as norm al controls. We also compared serum TGF-beta1 concentrations and TGF-beta m RNA expression levels in the B-cell-depleted (T-cell-rich) fraction of SMNC s in these mice. Results: HIGA mice showed significantly fewer CD3-positive cells compared with BALB/c mice when young, but not when aged. The CD4/CD8 ratio of HIGA mice was lower than that of BALB/c mice, but this difference was not significant. Although the number of B220-positive cells did not va ry significantly, the ratio of surface IgA-positive B cells was significant ly increased in both young and adult HIGA mice. The B-cell-depleted SMNCs f rom HIGA mice exhibited higher levels of expression of TGF-beta and TGF-bet a1 mRNA than controls from a young age, which were maintained throughout li fe, but there were no differences in PDGF, MCP-1 or bFGF expression between these two strains. In contrast to local mRNA expression, serum TGF-beta1 c oncentration was decreased in HIGA mice compared with BALB/c controls. Conc lusion: These findings suggest that the mating procedure performed to estab lish HIGA mice selected for a unique phenotype of local up-regulation of TG F-beta production in the kidneys, as well as T cells that may contribute to both the early and consistently high serum IgA expression and enhanced pro duction of renal extracellular matrix components in HIGA mice. Additionally , TGF-beta1 may act locally, not systemically, in a paracrine or autocrine manner. Copyright (C) 2001 S. Karger AG, Basel.