RGD Reference Report - Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. - Rat Genome Database

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Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo.

Authors: Wang, S  Wilkes, MC  Leof, EB  Hirschberg, R 
Citation: Wang S, etal., FASEB J. 2005 Jan;19(1):1-11.
RGD ID: 8693572
Pubmed: PMID:15629889   (View Abstract at PubMed)
DOI: DOI:10.1096/fj.04-2370com   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
ureteral obstruction  ISOAbl1 (Rattus norvegicus)8693572; 8693572protein:increased activity:kidney:RGD 
ureteral obstruction  IEP 8693572; 8693572protein:increased activity:kidney:RGD 
ureteral obstruction  ISOPak2 (Rattus norvegicus)8693572; 8693572protein:increased activity:kidney:RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to transforming growth factor beta stimulus  IEP 8693572; 8693572 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein kinase activity  IMP 8693572 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abl1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)
Pak2  (p21 (RAC1) activated kinase 2)

Genes (Mus musculus)
Abl1  (c-abl oncogene 1, non-receptor tyrosine kinase)
Pak2  (p21 (RAC1) activated kinase 2)

Genes (Homo sapiens)
ABL1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)
PAK2  (p21 (RAC1) activated kinase 2)


Additional Information