Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis.
Imatinib is a selective tyrosine kinase inhibitor that can block activity of the platelet-derived growth factor receptor (PDGFR) and that has immunomodulatory effects on various cell types. Here we measured the protective effects of imatinib in Wistar-Kyoto rats with nephrotoxic serum nephritis, a kidney disease model where CD8+ T cells and macrophages play pathogenetic roles. Groups of animals were given imatinib from one day before up to 13 days following induction of nephritis and from day 7 to 20 following disease induction. Compared to control rats, at each time point imatinib treatment caused significantly less proteinuria, lowered serum blood urea nitrogen and creatinine, and decreased the number of glomeruli with necrosis, crescents, and fibrin deposits. Imatinib-treated rats had a significant reduction in glomerular macrophage accumulation and reduced renal cortical PDGFR-beta and M-CSF receptor mRNA expression. Using colocalization we found that glomerular macrophages had reduced IL-1beta and MCP-1 protein expression. Late imatinib treatment significantly reduced proteinuria, serum blood urea nitrogen, and creatinine, and reversed renal histopathological changes. We show that imatinib has renoprotective and therapeutic properties and provide pre-clinical work that will need to be confirmed in patients with crescentic glomerulonephritis.
Iyoda
Masayuki
M
Division of Nephrology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan. iyoda@med.showa-u.ac.jp
Shibata
Takanori
T
Kawaguchi
Mio
M
Yamaoka
Toshimitsu
T
Akizawa
Tadao
T
D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology*; D001549:Benzamides; D003404:Creatinine / Q000097:blood; D005921:Glomerulonephritis / Q000188:drug therapy*; D000068877:Imatinib Mesylate; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D014508:Urea / Q000097:blood
D001549:Benzamides; D010879:Piperazines; D020011:Protective Agents; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D014508:Urea; D003404:Creatinine