SMP-534 inhibits TGF-beta-induced ECM production in fibroblast cells and reduces mesangial matrix accumulation in experimental glomerulonephritis.
Transforming growth factor-beta (TGF-beta) is a potent fibrotic factor responsible for the synthesis of extracellular matrix (ECM) and is implicated as the major determinant in pathogenesis of chronic fibroses, including kidney. The novel small compound SMP-534 reduced ECM production induced by TGF-beta in fibroblast cells. SMP-534 inhibited TGF-beta-induced p38 mitogen-activated protein kinase (p38) activation but did not inhibit epidermal growth factor (EGF)-induced extracellular signal-related kinase (ERK) activation. We also found that oral administration of SMP-534 dose dependently lowered hydroxyproline contents in the cortical region of the kidney in rat anti-Thy-1 nephritis models. In periodic acid-Schiff staining of kidney sections, ECM accumulation was reduced by SMP-534 treatment. These data indicate that SMP-534 has potential in therapy for fibrotic diseases, including nephropathy.
Sugaru
Eiji
E
Sumitomo Pharmaceuticals Research Division, Discovery Research Laboratories I, Konohana-ku, Osaka 554-0022, Japan.
Sakai
Mutsuko
M
Horigome
Kazuhiko
K
Tokunaga
Teruhisa
T
Kitoh
Makoto
M
Hume
W Ewan
WE
Nagata
Ryu
R
Nakagawa
Tsutomu
T
Taiji
Mutsuo
M
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000502:physiology*; D005347:Fibroblasts; D005920:Glomerular Mesangium / Q000502:physiology; D005921:Glomerulonephritis / Q000276:immunology / Q000503:physiopathology* / Q000662:veterinary; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001549:Benzamides; C505358:SMP-534; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases