Effects of TJN-598, a new selective phosphodiesterase type IV inhibitor on anti-Thy1 nephritis in rats.
BACKGROUND
Phosphodiesterase type IV (PDEIV) plays an important role in the immune response and inflammation. However, it is well known that classical PDEIV inhibitors have systemic side effects, so the clinical and chronic use of these agents as therapy for glomerulonephritis is difficult. This study was performed to elucidate the anti-nephritic effects of TJN-598, a new chemical compound derived from herbal components, on experimental mesangial proliferative glomerulonephritis.


METHODS
We first examined the effects of TJN-598 and captopril on mesangial expansion induced by anti-Thy1 serum in rats. Second, to investigate the effects of TJN-598 and rolipram, which are typical PDEIV inhibitors, on the production of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1, glomeruli were isolated from rats with anti-Thy1 nephritis and incubated with the test drugs in vitro for 48 h.


RESULTS
Treatment with TJN-598 prevented an increase in the mesangial area/total glomerular area, in the number of cells in the glomerular cross section and matrix index. TJN-598 also inhibited the increases in the expression of α-smooth muscle actin, the TGF-β1-positive area, in the number of ED-1 positive cells and proliferating cell nuclear antigen-positive cells in the glomeruli. Furthermore, administration of TJN-598 inhibited increases in the levels of TGF-β1 protein derived from glomeruli with anti-Thy-1 nephritis. The addition of both TJN-598 and rolipram to the culture supernatant inhibited both increased expression of TGF-β1 and increases in levels of TNF-α in glomeruli isolated from rats with anti-Thy1 nephritis in a dose-dependent manner.


CONCLUSIONS
These results suggest that TJN-598, a PDEIV inhibitor, is effective against expansion of mesangial cells, via the suppression of secretion of TGF-β1 and TNF-α from inflamed glomeruli.
Sadakane
Chiharu
C
Tsumura Research Laboratories, Tsumura & Co, 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, Japan.
Kase
Yoshio
Y
Koseki
Junichi
J
Hasegawa
Yoshihiro
Y
Shindo
Shoichiro
S
Maruyama
Hirobumi
H
Takeda
Shuichi
S
Takeda
Hiroshi
H
Hattori
Tomohisa
T
D000178:Acrylamides / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D028321:Plant Preparations / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018800:Thy-1 Antigens / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000178:Acrylamides; D007518:Isoantibodies; C558634:N-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-N-methyl-3-(3-pyridyl)-2-propenamide; D010726:Phosphodiesterase Inhibitors; D028321:Plant Preparations; D011725:Pyridines; D018800:Thy-1 Antigens; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C035678:anti-Thy antibody; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
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