title: Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice.
abstract: 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.
authors.affiliation: Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sadanaga
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Masutani
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Miyake
authors.forename: Sakiko
authors.initials: S
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Igawa
authors.forename: Naonobu
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirakata
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
mesh_terms: 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
chemical_list: 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