SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice.
Diabetic nephropathy is currently the most common cause of end-stage renal disease. Diabetic nephropathy patients, whether insulin dependent or not, develop fibrotic changes in glomeruli that manifest as overt nephropathy. Previously, we demonstrated that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrrol-1-yl]prop-1-en-1-yl}-N-(methylsulfonyl)benzamide (SMP-534) reduces extracellular matrix (ECM) production induced by transforming growth factor-beta (TGF-beta) in vitro and prevents the accumulation of ECM in glomeruli in rat Thy-1 nephritis models. In this study, we examined the long-term effects of SMP-534 on renal insufficiency and glomerulosclerosis in db/db mice, which are models of type 2 diabetes. A diet containing SMP-534 was given to the mice from the age of 9 to 25 wk, and blood and urine analysis were performed at 8, 17, and 25 wk. At the end of study, kidney tissues were analyzed histologically. Treatment with SMP-534 dose dependently suppressed the increase of urinary albumin and type IV collagen excretion in db/db mice. The renal histological analysis showed that SMP-534 dose dependently suppressed the increase of mesangial expansion in the kidney. In the immunohistological analysis, fibronectin and type IV collagen expression were lower in SMP-534-treated db/db mice compared with vehicle-treated db/db mice. This study suggested that SMP-534 ameliorated the increase of ECM production in kidney of db/db mice, possibly through the inhibition of TGF-beta action. Hence, antifibrotic agents such as SMP-534 might be a new therapeutic option for the treatment of diabetic nephropathy.
Sugaru
Eiji
E
Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Company, Limited, Drug Research Division, Konohana-ku, Osaka, Japan.
Nakagawa
Tsutomu
T
Ono-Kishino
Michiko
M
Nagamine
Jun
J
Tokunaga
Teruhisa
T
Kitoh
Makoto
M
Hume
W Ewan
WE
Nagata
Ryu
R
Taiji
Mutsuo
M
D000284:Administration, Oral; D000419:Albuminuria; D000821:Animal Feed; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D024141:Collagen Type IV / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D016212:Transforming Growth Factor beta / Q000502:physiology
D001549:Benzamides; D024141:Collagen Type IV; C505358:SMP-534; D016212:Transforming Growth Factor beta