Abstract
Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542. We studied its effect in vitro and found that it inhibited both the TGF-beta type I and type II receptor kinase activities, but not that of the related bone morphogenic protein type II receptor. Further, it blocked TGF-beta-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis. Using db/db mice, which develop diabetic nephropathy, we found that GW788388 given orally for 5 weeks significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys. Our study shows that GW788388 is a potent and selective inhibitor of TGF-beta signalling in vitro and renal fibrosis in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Activin Receptors, Type I / antagonists & inhibitors
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Administration, Oral
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Animals
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Benzamides / administration & dosage
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Benzamides / therapeutic use*
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Diabetic Nephropathies / drug therapy*
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Diabetic Nephropathies / pathology*
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Disease Models, Animal
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Fibrosis
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Humans
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Mice
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Mice, Inbred Strains
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrazoles / administration & dosage
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Pyrazoles / therapeutic use*
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Rats
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Rats, Sprague-Dawley
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Smad2 Protein / metabolism
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Smad3 Protein / metabolism
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology
Substances
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4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide
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Benzamides
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Pyrazoles
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Receptors, Transforming Growth Factor beta
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Acvr1b protein, mouse
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Acvr1c protein, mouse
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Tgfbr1 protein, rat