SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabeticdb/dbmice

Abstract

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.