Warning: Undefined variable $zfal in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Deprecated: str_replace(): Passing null to parameter #3 ($subject) of type array|string is deprecated in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 530
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 531
English Wikipedia
Nephropedia Template TP (
Twit Text
DeepDyve Pubget Overpricing |
lüll Intracellular TGF-beta receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo Ishida W; Mori Y; Lakos G; Sun L; Shan F; Bowes S; Josiah S; Lee WC; Singh J; Ling LE; Varga JJ Invest Dermatol 2006[Aug]; 126 (8): 1733-44Fibrosis, the hallmark of scleroderma, is characterized by excessive synthesis of collagen and extracellular matrix proteins and accumulation of myofibroblasts. Transforming growth factor-beta (TGF-beta), a potent inducer of collagen synthesis, cytokine production, and myofibroblast transdifferentiation, is implicated in fibrosis. Profibrotic TGF-beta responses are induced primarily via the type I activin-like receptor kinase 5 (ALK5) TGF-beta receptor coupled to Smad signal transducers. Here, we investigated the effect of blocking ALK5 function with SM305, a novel small-molecule kinase inhibitor, on fibrotic TGF-beta responses. In normal dermal fibroblasts, SM305 abrogated the ligand-induced phosphorylation, nuclear import, and DNA-binding activity of Smad2/3 and Smad4, and inhibited Smad2/3-dependent transcriptional responses. Furthermore, SM305 blocked TGF-beta-induced extracellular matrix gene expression, cytokine production, and myofibroblast transdifferentiation. In unstimulated scleroderma fibroblasts, SM305 caused a variable and modest reduction in type I collagen levels, and failed to abrogate constitutive nuclear accumulation of Smad2/3, or alter the proportion of smooth muscle actin stress fiber-positive fibroblasts. In vivo, SM305 prevented TGF-beta-induced Smad2/3 phosphorylation type I collagen (COL1)A2 promoter activation in dermal fibroblasts. Taken together, these results indicate that SM305 inhibits intracellular TGF-beta signaling through selective interference with ALK5-mediated Smad activation, resulting in marked suppression of profibrotic responses induced by TGF-beta in vivo and in vitro.|Animals[MESH]|Biopsy[MESH]|Cell Division/drug effects[MESH]|Cells, Cultured[MESH]|Dermis/cytology[MESH]|Fibroblasts/cytology/metabolism[MESH]|Humans[MESH]|In Vitro Techniques[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Protein Kinase Inhibitors/*pharmacology[MESH]|Pyrazoles/*pharmacology[MESH]|Quinolines/*pharmacology[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors/metabolism[MESH]|Scleroderma, Systemic/*drug therapy/*metabolism/pathology[MESH]|Smad Proteins/*metabolism[MESH]|Smad2 Protein/metabolism[MESH]|Smad3 Protein/metabolism[MESH]|Smad4 Protein/metabolism[MESH] |