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IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes
AIMS/HYPOTHESIS: Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, pa...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187213/ https://www.ncbi.nlm.nih.gov/pubmed/33758952 http://dx.doi.org/10.1007/s00125-021-05427-1 |
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author | Lay, Abigail C. Hale, Lorna J. Stowell-Connolly, Holly Pope, Robert J. P. Nair, Viji Ju, Wenjun Marquez, Eva Rollason, Ruth Hurcombe, Jenny A. Hayes, Bryony Roberts, Timothy Gillam, Lawrence Allington, Jonathan Nelson, Robert G. Kretzler, Matthias Holly, Jeff M. P. Perks, Claire M. McArdle, Craig A. Welsh, Gavin I. Coward, Richard J. M. |
author_facet | Lay, Abigail C. Hale, Lorna J. Stowell-Connolly, Holly Pope, Robert J. P. Nair, Viji Ju, Wenjun Marquez, Eva Rollason, Ruth Hurcombe, Jenny A. Hayes, Bryony Roberts, Timothy Gillam, Lawrence Allington, Jonathan Nelson, Robert G. Kretzler, Matthias Holly, Jeff M. P. Perks, Claire M. McArdle, Craig A. Welsh, Gavin I. Coward, Richard J. M. |
author_sort | Lay, Abigail C. |
collection | PubMed |
description | AIMS/HYPOTHESIS: Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. METHODS: IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. RESULTS: Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)–forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. CONCLUSIONS/INTERPRETATION: This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05427-1. |
format | Online Article Text |
id | pubmed-8187213 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-81872132021-06-11 IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes Lay, Abigail C. Hale, Lorna J. Stowell-Connolly, Holly Pope, Robert J. P. Nair, Viji Ju, Wenjun Marquez, Eva Rollason, Ruth Hurcombe, Jenny A. Hayes, Bryony Roberts, Timothy Gillam, Lawrence Allington, Jonathan Nelson, Robert G. Kretzler, Matthias Holly, Jeff M. P. Perks, Claire M. McArdle, Craig A. Welsh, Gavin I. Coward, Richard J. M. Diabetologia Article AIMS/HYPOTHESIS: Podocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes. METHODS: IGFBP expression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging. RESULTS: Data from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerular IGFBP-1 in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)–forkhead box O1 (FoxO1) activity. In vitro, IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability. CONCLUSIONS/INTERPRETATION: This work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression of IGFBP-1 is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05427-1. Springer Berlin Heidelberg 2021-03-24 2021 /pmc/articles/PMC8187213/ /pubmed/33758952 http://dx.doi.org/10.1007/s00125-021-05427-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lay, Abigail C. Hale, Lorna J. Stowell-Connolly, Holly Pope, Robert J. P. Nair, Viji Ju, Wenjun Marquez, Eva Rollason, Ruth Hurcombe, Jenny A. Hayes, Bryony Roberts, Timothy Gillam, Lawrence Allington, Jonathan Nelson, Robert G. Kretzler, Matthias Holly, Jeff M. P. Perks, Claire M. McArdle, Craig A. Welsh, Gavin I. Coward, Richard J. M. IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes |
title | IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes |
title_full | IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes |
title_fullStr | IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes |
title_full_unstemmed | IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes |
title_short | IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes |
title_sort | igfbp-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/fak signalling in human podocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187213/ https://www.ncbi.nlm.nih.gov/pubmed/33758952 http://dx.doi.org/10.1007/s00125-021-05427-1 |
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