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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
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370011/ https://www.ncbi.nlm.nih.gov/pubmed/28129651 http://dx.doi.org/10.18632/oncotarget.14808 |
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author | Sheu, Meei-Ling Shen, Chin-Chang Jheng, Jia-Rong Chiang, Chih-Kang |
author_facet | Sheu, Meei-Ling Shen, Chin-Chang Jheng, Jia-Rong Chiang, Chih-Kang |
author_sort | Sheu, Meei-Ling |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5370011 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53700112017-04-17 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 Sheu, Meei-Ling Shen, Chin-Chang Jheng, Jia-Rong Chiang, Chih-Kang Oncotarget Research Paper 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. Impact Journals LLC 2017-01-24 /pmc/articles/PMC5370011/ /pubmed/28129651 http://dx.doi.org/10.18632/oncotarget.14808 Text en Copyright: © 2017 Sheu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Sheu, Meei-Ling Shen, Chin-Chang Jheng, Jia-Rong Chiang, Chih-Kang 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370011/ https://www.ncbi.nlm.nih.gov/pubmed/28129651 http://dx.doi.org/10.18632/oncotarget.14808 |
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