PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell proliferation involving STAT3 activation.
Proliferation of mesangial cells is a hallmark of glomerular disease, and understanding the regulatory mechanisms is critically important. The purpose of this study was to examine the relationship between mesangial cell proliferation and phosphorylated signal transducer and activator of transcription (STAT) 3 and to determine whether the PDGF receptor tyrosine kinase inhibitor STI 571 inhibited mesangial cell proliferation via modulation of STAT3. In this study, we investigated for the first time, the glomerular expression of phosphorylated STAT3 in paraffin sections from animals with experimental mesangial proliferative glomeronephritis. Phosphorylated STAT3 colocalized with many proliferating mesangial cells. We also demonstrated that treatment with STI 571 reduced mesangial cell proliferation and phosphorylated STAT3 signalling both in vitro and in vivo. In vivo, STI 571 treatment reduced the number of glomerular mesangial cells positive for both phosphorylated STAT3 and proliferating cell nuclear antigen. In summary, phosphorylated STAT3 is strongly expressed during mesangial cell proliferation and STI 571 induced suppression of mesangial cell proliferation involves inhibition of phosphorylated STAT3 signalling.
Hirai
T
T
Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Masaki
T
T
Kuratsune
M
M
Yorioka
N
N
Kohno
N
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001549:Benzamides; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry / Q000379:methods; D007518:Isoantibodies / Q000276:immunology; D008297:Male; D050527:Mesangial Cells / Q000276:immunology*; D010766:Phosphorylation; D010879:Piperazines / Q000276:immunology*; D018809:Proliferating Cell Nuclear Antigen / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000276:immunology*; D011743:Pyrimidines / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001549:Benzamides; D007518:Isoantibodies; D010879:Piperazines; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C035678:anti-Thy antibody; D000068877:Imatinib Mesylate; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor