Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice.
OBJECTIVE
To examine whether the platelet-derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans.


METHODS
Sixteen-week-old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed.


RESULTS
In mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor beta messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib-treated mice compared with that in the 10 mg/kg imatinib-treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib-treated mice, in a dose-dependent manner. Serum levels of IgG and anti-double-stranded DNA antibodies were also reduced in the imatinib-treated mice.


CONCLUSIONS
These findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.
Sadanaga
Atsushi
A
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakashima
Hitoshi
H
Masutani
Kohsuke
K
Miyake
Katsuhisa
K
Shimizu
Sakiko
S
Igawa
Takashi
T
Sugiyama
Naonobu
N
Niiro
Hiroaki
H
Hirakata
Hideki
H
Harada
Mine
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001323:Autoantibodies / Q000097:blood; D001549:Benzamides; D001806:Blood Urea Nitrogen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003404:Creatinine / Q000097:blood; D004247:DNA / Q000276:immunology; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D000068877:Imatinib Mesylate; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000235:genetics; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D008206:Lymphatic Diseases / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D011743:Pyrimidines / Q000494:pharmacology*; D012469:Salivary Glands / Q000276:immunology; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013163:Splenomegaly / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001323:Autoantibodies; D001549:Benzamides; D007074:Immunoglobulin G; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D007371:Interferon-gamma; D000068877:Imatinib Mesylate; D004247:DNA; D003404:Creatinine