Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/95840
標題: Activation of PI3K in response to high glucose leads to regulation of SOCS-3 and STAT1/3 signals and induction of glomerular mesangial extracellular matrix formation
作者: 許美鈴
Sheu, Meei-Ling
Shen, Chin-Chang
Jheng, Jia-Rong
Chiang, Chih-Kang
關鍵字: extracellular matrix
high glucose
mesangial cell
phosphoinositide 3-kinase
signal transduction
Animals
Base Sequence
Cell Line
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Activation
Extracellular Matrix
Glucose
Immunoblotting
Male
Mesangial Cells
Phosphatidylinositol 3-Kinases
Promoter Regions, Genetic
Protein Binding
Rats, Sprague-Dawley
STAT1 Transcription Factor
STAT3 Transcription Factor
Signal Transduction
Suppressor of Cytokine Signaling 3 Protein
Time Factors
出版社: ONCOTARGET
摘要: Excessive deposition of extracellular matrix (ECM) in the glomerulus contributed by mesangial cells is the hallmark of diabetic nephropathy, eventually leading to glomerulosclerosis. In this study, we examined the regulatory signals involved in the high glucose (HG)-induced overproduction of ECM in rat mesangial cells (RMCs). We disclosed excessive fibronectin and collagen IV production, tyrosine phosphorylation of signal transducer and activator of transcription 1 and 3 (STAT1/3), and up-regulation of suppressor of cytokine signaling-3 (SOCS-3) expression in HG-treated RMCs. STAT1/STAT3 binding element was essential for SOCS-3 promoter activity stimulated by HG. HG was capable of promoting the specific DNA binding activities to an oligonucleotide probe containing the SOCS-3 sequence. The selective phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and dominant negative p85 vector (DNΔp85) transfection effectively abolished these HG-induced responses. Moreover, HG markedly increased the cyclin kinase inhibitor p27Kip1 protein expression, which could be inhibited by LY294002 or transfection of DNΔp85. Taken together, these results suggest that HG-induced SOCS-3 upregulation depends upon the presence of STAT-binding element in the SOCS-3 promoter, which is specifically activated by STAT1/3. The PI3K/STAT1/3 signaling pathway mediated HG-triggered ECM accumulation and SOCS-3 upregulation in RMCs.
URI: http://hdl.handle.net/11455/95840
Appears in Collections:生醫工程研究所

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