Oral administration of GW788388, an inhibitor of TGF-β type I and II receptor kinases, decreases renal fibrosis

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.

Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis

“…Cells were stimulated with TGF-b3 and BMP-6 at 5 and 100 ng/ml, respectively. SB431542 (Tocris bioscience, Bristol, UK) was used at 10 mM as previously reported (Petersen et al, 2008).…”

Investigation of DNA polymorphisms in SMAD genes for genetic predisposition to diabetic nephropathy in patients with type 1 diabetes mellitus

“…Elevated SMAD1 levels are associated with early renal dysfunction and SMAD1 levels in glomeruli are correlated with progression of renal disease [4]. In a mouse model of diabetic nephropathy, inhibition of the TGFβ-SMAD2/3 pathway resulted in reduced renal fibrosis [5]. In a small family-based study, two single nucleotide polymorphisms (SNPs) in SMAD3 were associated with diabetic nephropathy [6].…”

Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-κB and Smad2/3 Signaling

“…In addition to physical forces, an alternative mechanism for proteinuria could be attributable to humoral factors that are induced during the disease. For example, inflammatory cytokines or fibrogenic mediators had been shown to modulate podocyte motility and albumin permeability, mRNA expression of podocyte markers such as nephrin and ezrin as well as podocyte survival and adhesion (9)(10)(11)(12)(13)(14)(15). Presumably, through mesangial cellpodocyte communication (16)(17)(18), these effects might lead to breakdown of the glomerular permeability with resultant formation of proteinuria.…”

“…Apart from its profibrotic action, TGF-β1 induces podocyte dedifferentiation and causes albumin influx across the podocyte monolayer (11,12). In TGF-β1 transgenic mice, podocytes undergo apoptosis in association with depletion of podocytes early during progressive glomerulosclerosis (32).…”

“…Inflammatory cytokines and fibrogenic mediators have been shown to modulate podocyte motility and albumin permeability in vitro (9)(10)(11)(12)(13). And mesangialderived cytokines such as tumor necrosis factor (TNF)-α or transforming growth factor (TGF)-β1 can inhibit the expression of nephrin and ezrin by podocytes and induce podocyte death and detachment (14,15).…”