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Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress
Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use esta...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834602/ https://www.ncbi.nlm.nih.gov/pubmed/29500363 http://dx.doi.org/10.1038/s41598-018-22233-9 |
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author | Garner, Kathryn L. Betin, Virginie M. S. Pinto, Vanda Graham, Mark Abgueguen, Emmanuelle Barnes, Matt Bedford, David C. McArdle, Craig A. Coward, Richard J. M. |
author_facet | Garner, Kathryn L. Betin, Virginie M. S. Pinto, Vanda Graham, Mark Abgueguen, Emmanuelle Barnes, Matt Bedford, David C. McArdle, Craig A. Coward, Richard J. M. |
author_sort | Garner, Kathryn L. |
collection | PubMed |
description | Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity. We find that by improving insulin sensitivity at the level of the insulin receptor (IR), either by IR over-expression or by knocking down the negative regulator of IR activity, protein tyrosine-phosphatase 1B (PTP1B), podocytes are protected from ER stress caused by fatty acids or diabetic media containing high glucose, high insulin and inflammatory cytokines TNFα and IL-6. However, contrary to this, knockdown of the negative regulator of PI3K-Akt signalling, phosphatase and tensin homolog deleted from chromosome 10 (PTEN), sensitizes podocytes to ER stress and apoptosis, despite increasing Akt phosphorylation. This indicates that protection from ER stress is conferred through not just the PI3K-Akt pathway, and indeed we find that inhibiting the MEK/ERK signalling pathway rescues PTEN knockdown podocytes from ER stress. |
format | Online Article Text |
id | pubmed-5834602 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58346022018-03-05 Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress Garner, Kathryn L. Betin, Virginie M. S. Pinto, Vanda Graham, Mark Abgueguen, Emmanuelle Barnes, Matt Bedford, David C. McArdle, Craig A. Coward, Richard J. M. Sci Rep Article Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity. We find that by improving insulin sensitivity at the level of the insulin receptor (IR), either by IR over-expression or by knocking down the negative regulator of IR activity, protein tyrosine-phosphatase 1B (PTP1B), podocytes are protected from ER stress caused by fatty acids or diabetic media containing high glucose, high insulin and inflammatory cytokines TNFα and IL-6. However, contrary to this, knockdown of the negative regulator of PI3K-Akt signalling, phosphatase and tensin homolog deleted from chromosome 10 (PTEN), sensitizes podocytes to ER stress and apoptosis, despite increasing Akt phosphorylation. This indicates that protection from ER stress is conferred through not just the PI3K-Akt pathway, and indeed we find that inhibiting the MEK/ERK signalling pathway rescues PTEN knockdown podocytes from ER stress. Nature Publishing Group UK 2018-03-02 /pmc/articles/PMC5834602/ /pubmed/29500363 http://dx.doi.org/10.1038/s41598-018-22233-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Garner, Kathryn L. Betin, Virginie M. S. Pinto, Vanda Graham, Mark Abgueguen, Emmanuelle Barnes, Matt Bedford, David C. McArdle, Craig A. Coward, Richard J. M. Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress |
title | Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress |
title_full | Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress |
title_fullStr | Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress |
title_full_unstemmed | Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress |
title_short | Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress |
title_sort | enhanced insulin receptor, but not pi3k, signalling protects podocytes from er stress |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834602/ https://www.ncbi.nlm.nih.gov/pubmed/29500363 http://dx.doi.org/10.1038/s41598-018-22233-9 |
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