(E)-N-[(3,4-dimethoxyphenethyl)]-N-methyl-3-(3-pyridyl)-2-propenamide (TJN-331) inhibits mesangial expansion in experimental IgA nephropathy in ddY mice.
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.
Saegusa
Yayoi
Y
Division of Pharmasciences, Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo 060-0812, Japan.
Sadakane
Chiharu
C
Koseki
Junichi
J
Hasegawa
Yoshihiro
Y
Shindo
Shoichiro
S
Takeda
Shuichi
S
Takeda
Hiroshi
H
Hattori
Tomohisa
T
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
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
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