Differential effects of rapamycin in anti-GBM glomerulonephritis.
The immunosuppressive mammalian target of rapamycin inhibitor rapamycin is widely used in solid-organ transplantation, but the effect of rapamycin on kidney disease is controversial. This study evaluated the effect of rapamycin in the autologous phase of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Disease was induced by preimmunizing the animals with rabbit IgG 5 d before administration of rabbit anti-mouse GBM antiserum. When rapamycin was started on the day of immunization (group 1), mice were protected from glomerulonephritis, suggested by a dramatic decrease in albuminuria, influx of inflammatory cells, and Th1-cytokine expression in the kidneys. Activation of T cells and production of autologous mouse anti-rabbit IgG were also significantly reduced in rapamycin-treated animals. In contrast, when rapamycin was started 14 d after immunization (group 2), mice had a significant increase in albuminuria and renal infiltration of inflammatory cells compared with vehicle-treated animals, and there were no differences in T and B cell responses. A significant decrease in vascular endothelial growth factor-A and an increase in IL-6 were detected in kidneys of these rapamycin-treated mice. In conclusion, rapamycin has the potential to significantly reduce the B and T cell responses and thereby protect from glomerulonephritis when administered early in disease. Once disease is established, however, rapamycin seems to worsen glomerulonephritis by disturbing the endothelial cell/vascular endothelial growth factor system in the kidney.
Hochegger
Kathrin
K
Division of Nephrology, Tyrolean Cancer Research Institute, Innsbruck Medical University, Innsbruck, Austria.
Jansky
Gerhard L
GL
Soleiman
Afschin
A
Wolf
Anna M
AM
Tagwerker
Andrea
A
Seger
Christoph
C
Griesmacher
Andrea
A
Mayer
Gert
G
Rosenkranz
Alexander R
AR
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D016207:Cytokines; D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D020123:Sirolimus