Prevention of glomerular crescent formation in glomerulonephritis by mycophenolate mofetil in rats.
BACKGROUND
Glomerular crescent formation is a prominent feature of aggressive forms of glomerulonephritis (GN) and is associated with a poor prognosis. We investigated whether the potent immunosuppressive agent mycophenolate mofetil (MMF) could prevent crescent formation in a model of anti-glomerular basement membrane (GBM) GN in the rat.


METHODS
GN with glomerular crescents was induced by the injection of anti-GBM antibody to female Wistar-Kyoto (WKY/NCrj) rats. The experimental rats were divided into two groups: rats received vehicle (0.5% carboxymethylcerlose) or MMF (20 mg/kg/day) orally. Body weight was measured and the urine and blood samples were evaluated. The rats were sacrificed at day 14, and histological analysis was performed. The mRNA expression of cytokines and adhesion molecules in the kidney was analysed by reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Marked proteinuria, glomerular crescent formation and glomerulosclerosis were observed in this model, and these were significantly reduced by MMF treatment. Marked glomerular macrophage and T-cell infiltration was also observed, and MMF treatment significantly inhibited macrophage but not T-cell infiltration. RT-PCR and immunohistochemical analysis revealed that mRNA and protein expression of osteopontin was decreased by the treatment with MMF. In addition, MMF treatment in the early stages of GN could inhibit proteinuria, glomerular crescent formation and glomerulosclerosis.


CONCLUSIONS
These findings suggest therapeutic potential for MMF in the inhibition of glomerular crescent formation in GN and provide new insights into the mechanism underlying the amelioration of crescentic GN by MMF treatment.
Takeda
Shin-ichi
S
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan.
Takahashi
Masafumi
M
Sado
Yoshikazu
Y
Takeuchi
Koichi
K
Hakamata
Yoji
Y
Shimizu
Hisashi
H
Kaneko
Takashi
T
Yamamoto
Hisashi
H
Ito
Chiharu
C
Ookawara
Shigeo
S
Asano
Yasushi
Y
Kusano
Eiji
E
Kobayashi
Eiji
E
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D053495:Osteopontin; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D011921:Rats, Inbred WKY; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D007166:Immunosuppressive Agents; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D009173:Mycophenolic Acid