Abstract
Transforming growth factor-β (TGF-β) 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-β receptor. In the current study we show that in cultured NRK49F-renal fibroblasts (but not in tubular or mesangial cells) TGF-β 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-β addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a disease model of TGF-β-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-β-induced activation of the nonreceptor c-abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF-β-dependent renal fibrogenesis. Inhibition of c-abl activity with imatinib mesylate ameliorates experimental renal fibrosis in rats. - Wang, S., Wilkes, M. C., Leof, L. B., Hirschberg, R. Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-11 |
| Number of pages | 11 |
| Journal | FASEB Journal |
| Volume | 19 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2005 |
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Keywords
- ECM
- Experimental renal fibrosis
- Renal interstitial fibrosis
- Unilaterial ureteral obstruction
ASJC Scopus subject areas
- Agricultural and Biological Sciences (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Cell Biology
Cite this
Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo. / Wang, Shinong; Wilkes, Mark C.; Leof, Edward B; Hirschberg, Raimund.
In: FASEB Journal, Vol. 19, No. 1, 01.2005, p. 1-11.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo
AU - Wang, Shinong
AU - Wilkes, Mark C.
AU - Leof, Edward B
AU - Hirschberg, Raimund
PY - 2005/1
Y1 - 2005/1
N2 - Transforming growth factor-β (TGF-β) 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-β receptor. In the current study we show that in cultured NRK49F-renal fibroblasts (but not in tubular or mesangial cells) TGF-β 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-β addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a disease model of TGF-β-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-β-induced activation of the nonreceptor c-abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF-β-dependent renal fibrogenesis. Inhibition of c-abl activity with imatinib mesylate ameliorates experimental renal fibrosis in rats. - Wang, S., Wilkes, M. C., Leof, L. B., Hirschberg, R. Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo.
AB - Transforming growth factor-β (TGF-β) 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-β receptor. In the current study we show that in cultured NRK49F-renal fibroblasts (but not in tubular or mesangial cells) TGF-β 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-β addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a disease model of TGF-β-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-β-induced activation of the nonreceptor c-abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF-β-dependent renal fibrogenesis. Inhibition of c-abl activity with imatinib mesylate ameliorates experimental renal fibrosis in rats. - Wang, S., Wilkes, M. C., Leof, L. B., Hirschberg, R. Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo.
KW - ECM
KW - Experimental renal fibrosis
KW - Renal interstitial fibrosis
KW - Unilaterial ureteral obstruction
UR - http://www.scopus.com/inward/record.url?scp=11244292291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=11244292291&partnerID=8YFLogxK
U2 - 10.1096/fj.04-2370com
DO - 10.1096/fj.04-2370com
M3 - Article
C2 - 15629889
AN - SCOPUS:11244292291
VL - 19
SP - 1
EP - 11
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 1
ER -