Oncotarget

Research Papers:

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

Meei-Ling Sheu _, Chin-Chang Shen, Jia-Rong Jheng and Chih-Kang Chiang

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Oncotarget. 2017; 8:16925-16938. https://doi.org/10.18632/oncotarget.14808

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Abstract

Meei-Ling Sheu1,2,3,*, Chin-Chang Shen4,*, Jia-Rong Jheng5,6, Chih-Kang Chiang5,6,7

1Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

2Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

3Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan

4Chemical Engineering Division, Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan

5Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan

6Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

7Department 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 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.


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