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SMP-534 inhibits TGF--induced ECM production in fibroblast cells and reduces mesangial matrix accumulation in experimental glomerulonephritis

¹Discovery Research Laboratories I, ²Genomic Research Laboratories, and ³Chemical Research Laboratories, Sumitomo Pharmaceuticals Research Division, Osaka, Japan

Submitted 15 February 2005 ; accepted in final form 15 May 2005

Transforming growth factor- (TGF-) 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- in fibroblast cells. SMP-534 inhibited TGF--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.

renal fibrosis; anti-Thy-1 nephritis; proteoglycan; p38 mitogen-activated protein kinase

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