NDT Advance Access published online on April 29, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn216
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Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice
1 Department of Medicine, the University of Hong Kong, Tung Wah Hospital 2 Department of Medicine 3 Department of Pathology, the University of Hong Kong, Queen Mary Hospital 4 Department of Clinical Biochemistry, Queen Mary Hospital, Hong Kong SAR, People's Republic of China
Correspondence and offprint requests to: Tak Mao Chan, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, People's Republic of China. Tel: + 852-2855-4542; Fax: + 852-2872-5828; E-mail: dtmchan{at}hku.hk
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Abstract |
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Background. Rapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F1 (NZB/W F1) mice.
Methods. Six-month-old female NZB/W F1 mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies.
Results. Treatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES.
Conclusions. We conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F1 mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis.
Keywords: autoimmunity; lupus nephritis; NZB/W F1 mice; rapamycin
Received for publication: 14.12.07
Accepted in revised form: 26. 3.08