title: (E)-N-[(3,4-dimethoxyphenethyl)]-N-methyl-3-(3-pyridyl)-2-propenamide (TJN-331) inhibits mesangial expansion in experimental IgA nephropathy in ddY mice.
abstract: BACKGROUND
  TJN-331 is an inhibitor of transforming growth factor β1 (TGF-β1) production that has similar structural features to the natural product acteoside. This study was performed to examine the antinephritic effects of TJN-331 in a mouse model of experimental IgA nephropathy.
  
  
  METHODS
  IgA nephropathy was induced in ddY mice by oral administration of bovine γ globulin, followed by reticuloendothelial blocking by colloidal carbon injection and heminephrectomy. Effects of TJN-331 were examined over oral administration periods from 10 to 15 weeks after the third colloidal carbon injection. Intravenous administration of a TGF-β1-neutralizing antibody was used to investigate the role of TGF-β1 in IgA nephropathy.
  
  
  RESULTS
  Administration of TJN-331 or captopril prevented elevation of serum creatinine. Histopathological examination after both experimental periods showed that TJN-331 inhibited increases in the mesangial matrix index and the number of nuclei per glomerular cross-section, compared with in untreated ddY mice with IgA nephropathy. TJN-331 prevented increase in glomerular TGF-β1 staining without affecting IgA. In the in vitro study, TJN-331 prevented total TGF-β1 production from splenocytes stimulated with concanavalin A. A neutralizing antibody against TGF-β1 prevented increase in the mesangial matrix index and the number of glomerular cells per cross-sectional area.
  
  
  CONCLUSIONS
  These results suggest that TJN-331 is effective against IgA nephropathy in ddY mice and acts via suppression of TGF-β1 production in glomeruli.
authors.affiliation: Division of Pharmasciences, Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Saegusa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sadakane
authors.forename: Junichi
authors.initials: J
authors.lastname: Koseki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Shindo
authors.forename: Shuichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009392:Nephrectomy; D011725:Pyridines / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D000178:Acrylamides; C554102:N-(3,4-dimethoxyphenethyl)-N-methyl-3-(3-pyridyl)-2-propenamide; D011725:Pyridines; D053773:Transforming Growth Factor beta1; D003208:Concanavalin A; D003404:Creatinine
references.citation: Clin Nephrol. 1987 Mar;27(3):141-6
references.pmid: 3105940
references.citation: Kidney Int. 2005 Dec;68(6):2517-25
references.pmid: 16316328
references.citation: Kidney Int. 1996 Dec;50(6):1946-57
references.pmid: 8943478
references.citation: Nephron. 2001 Aug;88(4):368-75
references.pmid: 11474233
references.citation: Clin Exp Immunol. 1991 Jun;84(3):459-65
references.pmid: 2044226
references.citation: J Lipid Res. 1984 Dec 15;25(13):1619-23
references.pmid: 6397566
references.citation: Jpn J Pharmacol. 1994 Jun;65(2):143-51
references.pmid: 7526020
references.citation: Lab Invest. 1993 Jul;69(1):68-76
references.pmid: 8331901
references.citation: Nephron. 2002 Oct;92(2):389-98
references.pmid: 12218319
references.citation: Clin Exp Immunol. 2004 Apr;136(1):168-75
references.pmid: 15030528
references.citation: Jpn J Pharmacol. 1996 Feb;70(2):157-68
references.pmid: 8866753
references.citation: Clin Nephrol. 2006 Jun;65(6):385-92
references.pmid: 16792132
references.citation: Lab Invest. 1986 Apr;54(4):377-84
references.pmid: 3515045
references.citation: J Nephrol. 2008 Jul-Aug;21(4):463-7
references.pmid: 18651534
references.citation: Am J Physiol Renal Physiol. 2004 Feb;286(2):F278-87
references.pmid: 14583433
references.citation: J Nephrol. 2008 Jan-Feb;21(1):53-63
references.pmid: 18264937
references.citation: Kidney Int. 2004 Feb;65(2):459-68
references.pmid: 14717916
references.citation: Biol Pharm Bull. 2009 Oct;32(10):1728-33
references.pmid: 19801835
references.citation: Nihon Jinzo Gakkai Shi. 1996 May;38(5):202-12
references.pmid: 8699610