title: Blockade of TGF-beta action ameliorates renal dysfunction and histologic progression in anti-GBM nephritis.
abstract: BACKGROUND
  We tested whether the entire soluble extracellular domain of the human transforming growth factor-beta (TGF-beta) type II receptor, fused to the Fc portion of human immunoglobulin G (IgG1) (Tbeta-ExR) and expressed in skeletal muscles by adenovirus-mediated gene transfer (AdTbeta-ExR), can ameliorate renal dysfunction and histologic progression in a rat experimental anti-glomerular basement membrane (GBM) nephritis.
  
  
  METHODS
  Anti-GBM nephritis was induced in Wistar Kyoto rats by an intravenous injection of anti-rat glomerular basement membrane (GBM) sera. At day 1 (24 hours after induction), AdTbeta-ExR (1 x 109 pfu/mL) was injected into the femoral muscle in the treatment group, and an adenovirus vector-expressing bacterial beta-galactosidase (AdLacZ) was injected into the control group. Then, clinical and histologic changes were examined for 3 weeks after the induction of anti-GBM nephritis.
  
  
  RESULTS
  Tbeta-ExR was detected in the serum at day 7, but the serum concentration of Tbeta-ExR had decreased below the detectable level by day 14. Although blood pressure and the degree of proteinuria were similar in both groups, the deterioration of renal function was significantly blunted in the treatment group. Crescent formation and interstitial fibrosis were also ameliorated in the treatment group. These histologic improvements were accompanied by the decreased interstitial infiltration of macrophages and the decreased alpha-smooth muscle actin (alpha-SMA)-positive cells in the glomeruli and the interstitium.
  
  
  CONCLUSIONS
  This study demonstrated for the first time that the blockade of TGF-beta action by AdTbeta-ExR in the early stage of anti-GBM nephritis ameliorates the clinical and histologic progression. In addition, this study shed light on the development of a specific gene therapy for human crescentic glomerulonephritis.
authors.affiliation: Department of Pediatrics, Department of Urology, and Division of Molecular Medicine, Kobe University Graduate Schoolof Medicine, Kobe, Japan.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhou
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ueno
authors.forename: Mayumi
authors.initials: M
authors.lastname: Shimomura
authors.forename: Ryojiro
authors.initials: R
authors.lastname: Tanaka
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D018014:Gene Transfer Techniques; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D011921:Rats, Inbred WKY; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D000199:Actins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta