Spleen tyrosine kinase mediates high glucose-induced transforming growth factor-β1 up-regulation in proximal tubular epithelial cells.
The role of spleen tyrosine kinase (Syk) in high glucose-induced intracellular signal transduction has yet to be elucidated. We investigated whether Syk is implicated in high glucose-induced transforming growth factor-β1 (TGF-β1) up-regulation in cultured human proximal tubular epithelial cells (HK-2 cell). High glucose increased TGF-β1 gene expression through Syk, extracellular signal-regulated kinase (ERK), AP-1 and NF-κB. High glucose-induced AP-1 DNA binding activity was decreased by Syk inhibitors and U0126 (an ERK inhibitor). Syk inhibitors suppressed high glucose-induced ERK activation, whereas U0126 had no effect on Syk activation. High glucose-induced NF-κB DNA binding activity was also decreased by Syk inhibitors. High glucose increased nuclear translocation of p65 without serine phosphorylation of IκBα and without degradation of IκBα, but with an increase in tyrosine phosphorylation of IκBα that may account for the activation of NF-κB. Both Syk inhibitors and Syk-siRNA attenuated high glucose-induced IκBα tyrosine phosphorylation and p65 nuclear translocation. Depletion of p21-activated kinase 2 (Pak2) by transfection of Pak2-siRNA abolished high glucose-induced Syk activation. In summary, high glucose-induced TGF-β1 gene transcription occurred through Pak2, Syk and subsequent ERK/AP-1 and NF-κB pathways. This suggests that Syk might be implicated in the diabetic kidney disease.
Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Won Seok
WS
Yang
Jai Won
JW
Chang
Nam Jeong
NJ
Han
Sang Koo
SK
Lee
Su-Kil
SK
Park
D001483:Base Sequence; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology; D000072377:Syk Kinase; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D015854:Up-Regulation; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D002070:Butadienes; D017931:DNA Primers; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; C113580:U 0126; D000072000:NF-KappaB Inhibitor alpha; D009536:Niacinamide; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C515907:PAK2 protein, human; D054462:p21-Activated Kinases; D005947:Glucose