title: Treatment with anti-TGF-beta antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-beta signaling.
abstract: BACKGROUND
  Although short-term treatment with anti-transforming growth factor-beta (TGF-beta) antibody (alphaT) has been shown to prevent early glomerular lesions, its long-term effects and molecular mechanisms, including intracellular signaling, remain poorly understood. We examined whether alphaT treatment induces prevention of renal insufficiency and fibrosis, and affects the TGF-beta/Smad signaling pathway in rats with chronic progressive anti-thymocyte serum (ATS) nephritis induced by repeated ATS injections on days 0 and 7.
  
  
  METHODS
  Nephritic and non-nephritic rats were treated with either alphaT or control immunoglobulin (Ig)G twice weekly for 4 weeks from days 7 to 35 (each group, N= 21). Renal lesions and cortical expression of TGF-beta1, TGF-beta2, TGF-beta3, type II TGF-beta receptor (TbetaRII), Smads, type I collagen, and plasminogen activator inhibitor-1 were examined by immunohistochemistry, Western blot, and/or real-time reverse transcription polymerase chain reaction (RT-PCR). The binding of Smad3 in renal cortical cell nuclei to the Smad-binding element (SBE) was investigated by the electrophoretic mobility shift assay.
  
  
  RESULTS
  Nephritic rats developed heavy proteinuria, renal insufficiency, and increased extracellular matrix deposition resulting in renal fibrosis. Cortical expression levels of TGF-beta1, TGF-beta2, TbetaRII, and Smad2, but not TGF-beta3, Smad3, and Smad4 were increased. Expression and preferential localization of phosphorylated Smad2/3 in the glomerular and tubular cell nuclei, and Smad3-SBE complex-forming activity were also increased. Four-week alphaT treatment resulted in marked amelioration of chronic progressive ATS nephritis at 8 weeks.
  
  
  CONCLUSIONS
  In chronic progressive ATS nephritis, the TGF-beta/Smad signaling was up-regulated. TGF-beta blockade by alphaT suppressed the progression of renal scarring, at least in part, via inhibition of activated TGF-beta/Smad signaling.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. fukasawa@hama-med.ac.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Fukasawa
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Akashi
authors.initials: A
authors.lastname: Togawa
authors.forename: Naro
authors.initials: N
authors.lastname: Ohashi
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujigaki
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uchida
authors.forename: Michiko
authors.initials: M
authors.lastname: Aoki
authors.forename: Mareto
authors.initials: M
authors.lastname: Hosono
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
mesh_terms: D000818:Animals; D001835:Body Weight; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism* / Q000628:therapy*; D006909:Hydroxyproline / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology; D007167:Immunotherapy; D007672:Kidney Cortex / Q000502:physiology; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011507:Proteinuria / Q000378:metabolism / Q000628:therapy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012756:Sheep; D015398:Signal Transduction / Q000276:immunology; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D003094:Collagen; D006909:Hydroxyproline