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

系膜细胞 医学 细胞外基质 车站3 信号转导 肾小球硬化 PI3K/AKT/mTOR通路 内科学 化学 癌症研究 细胞生物学 生物 蛋白尿
作者
Meei‐Ling Sheu,Chin-Chang Shen,Jia-Rong Jheng,Chih‐Kang Chiang
出处
期刊:Oncotarget [Impact Journals LLC]
卷期号:8 (10): 16925-16938 被引量:15
标识
DOI:10.18632/oncotarget.14808
摘要

// Meei-Ling Sheu 1, 2, 3, * , Chin-Chang Shen 4, * , Jia-Rong Jheng 5, 6 , Chih-Kang Chiang 5, 6, 7 1 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan 2 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan 3 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan 4 Chemical Engineering Division, Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan 5 Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan 6 Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan 7 Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Chih-Kang Chiang, email: ckchiang@ntu.edu.tw Keywords: extracellular matrix, high glucose, mesangial cell, phosphoinositide 3-kinase, signal transduction Received: October 26, 2016 Accepted: December 13, 2016 Published: January 24, 2017 ABSTRACT 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 p27 Kip1 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.
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