Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo.
Transforming growth factor-beta (TGF-beta) is the single most important cytokine promoting renal fibrogenesis. p21-activated kinase-2 (PAK2) and activation of abelson nonreceptor tyrosine kinase (c-abl) have been shown recently to be smad-independent, fibroblast-specific targets downstream of the activated TGF-beta receptor. In the current study we show that in cultured NRK49F-renal fibroblasts (but not in tubular or mesangial cells) TGF-beta similarly activates PAK2 as well as c-abl and induces cell proliferation. Inhibition of the c-abl kinase with imatinib mesylate prevents increased proliferation after TGF-beta addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a disease model of TGF-beta-driven renal fibrogenesis. In obstructed kidneys, PAK2 and c-abl activity were increased but only c-abl activation was blocked by imatinib. Treatment with imatinib did not prevent renal interstitial infiltration of macrophages or phosphorylation and nuclear translocation of smad2/3 in obstructed kidneys. In contrast, imatinib substantially inhibited an increase in the number of interstitial fibroblasts and myofibroblasts and reduced the expression and interstitial accumulation of collagen type III, collagen type IV and fibronectin. These findings indicate that TGF-beta-induced activation of the nonreceptor c-abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF-beta-dependent renal fibrogenesis. Inhibition of c-abl activity with imatinib mesylate ameliorates experimental renal fibrosis in rats.
Wang
Shinong
S
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, California, USA.
Wilkes
Mark C
MC
Leof
Edward B
EB
Hirschberg
Raimund
R
D000818:Animals; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control*; D000068877:Imatinib Mesylate; D007674:Kidney Diseases / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology; D054462:p21-Activated Kinases
D001549:Benzamides; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D010879:Piperazines; D011743:Pyrimidines; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C497787:Smad3 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; C515909:Pak2 protein, mouse; C515910:Pak2 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases