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1 Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division, Konohana-ku, Osaka, Japan
2 Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Drug Research Division, Konohana-ku, Osaka, Japan
3 Technology Research and Development Center, Chemical Synthesis Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Technology Research and Development Center, Konohana-ku, Osaka, Japan
* To whom correspondence should be addressed. E-mail: mutsuo-taiji{at}ds-pharma.co.jp.
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 have 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-
(TGF-) 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 weeks, and blood and urine analysis were performed at 8, 17 and 25 weeks. 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 to 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- action. Hence, anti-fibrotic agents such as SMP-534 might be a new therapeutic option for the treatment of diabetic nephropathy.
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