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NDT Advance Access originally published online on June 8, 2004
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Nephrol Dial Transplant (2004) 19: 1976-1985
Nephrol Dial Transplant Vol. 19 No. 8 © ERA-EDTA 2004; all rights reserved

Original Article

Anti-macrophage migration inhibitory factor reduces transforming growth factor-ß1 expression in experimental IgA nephropathy

Joseph C. K. Leung, Loretta Y. Y. Chan, Anita W. L. Tsang, Emily W. L. Liu, Man Fai Lam, Sydney C. W. Tang and Kar Neng Lai

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong

Correspondence and offprint requests to: Professor K. N. Lai, Department of Medicine, Room 411, Professorial Block, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Email: knlai{at}hkucc.hku.hk

Background. In human glomerulonephritis, including immunoglobulin-A nephropathy (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is found to correlate with progressive renal injury. We have shown previously that polymeric IgA is capable of inducing MIF production in cultured human mesangial cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we examined whether IgA deposition and the subsequent renal injury can be ameliorated with anti-MIF treatment in an experimental murine model of IgAN.

Methods. Glomerular IgA deposition was induced in 4-week-old BALB/c mice by intravenous injection of immune complexes consisting of dinitrophenyl-conjugated bovine serum albumin (DNP–BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg) or isotypic control antibody intravenously 2 h before the immune complexes administration. The mice were sacrificed 48 h after injection of DNP–IgA. Proteinuria and haematuria were determined and the kidneys were removed for histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on production of TGF-ß1 by cultured mesangial cells was also examined.

Results. IgA deposits were detected in glomeruli of all mice receiving the immune complexes while no glomerular deposit was detected in the control mice. Microscopic haematuria and mesangial hypercellularity were present in mice of the three experimental groups and were absent in the control group. Proteinuria was absent in all groups. Anti-MIF treatment also resulted in decreased renal expression of TGF-ß1. Moreover, the reduction in TGF-ß1 expression was confined mainly to glomerular mesangium. An in vitro culture experiment demonstrated that MIF increased TGF-ß1 production in a time- and dose-dependent fashion. MIF-induced TGF-ß1 synthesis was abolished by incubating cells with neutralizing antibody against MIF.

Conclusions. Our finding shows that anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-ß1 expression in an experimental model of IgAN.

Keywords: animal model; IgA nephropathy; immunoglobulin A; macrophage migration inhibitory factor; mice; transforming growth factor-ß


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