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.