Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice

• Published in: Nephrology, dialysis, transplantation Vol. 23; no. 9; pp. 2768 - 2776
• Main Authors: Lui, Sing Leung, Tsang, Ryan, Chan, Kwok Wah, Zhang, Florence, Tam, Sidney, Yung, Susan, Chan, Tak Mao
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.2008
• Subjects: Albuminuria - drug therapy; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Autoimmunity; Biological and medical sciences; Chemokine CCL5 - metabolism; Emergency and intensive care: renal failure. Dialysis management; Female; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Intensive care medicine; Kidney - metabolism; lupus nephritis; Lupus Nephritis - drug therapy; Lupus Nephritis - pathology; Medical sciences; Mice; Mice, Inbred NZB; Nephritis; NZB/W F1 mice; rapamycin; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sirolimus - pharmacology; Sirolimus - therapeutic use; Splenomegaly; lupus nephritis; autoimmunity; mice; NZB W F; rapamycin; Kidney disease; Antineoplastic agent; Lupus; Skin disease; Urinary system disease; Sirolimus; Hemodialysis; Rodentia; Lactone; Macrolide; Macrocycle; NZB/W F1 mice; Extrarenal dialysis; Vertebrata; Antibiotic; Mammalia; Mouse; Animal; Renal failure; Protein synthesis inhibitor; Immunosuppressive agent
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfn216

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.