IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes

Autor: Viji Nair, Jonathan Allington, Jeffrey M P Holly, Ruth Rollason, Bryony Hayes, Holly Stowell-Connolly, Claire M Perks, Jenny A Hurcombe, Lawrence Gillam, Gavin I. Welsh, Lorna J Hale, Craig A. McArdle, Robert J P Pope, Abigail C Lay, Eva Marquez, Richard J M Coward, Robert G. Nelson, Wenjun Ju, Matthias Kretzler, Timothy Roberts
Rok vydání: 2021
Předmět:
0301 basic medicine
Endocrinology
Diabetes and Metabolism
Biopsy
Cell
Kidney Glomerulus
FOXO1
Diabetic nephropathy
Fkhr
Kidney
Podocyte
Pathogenesis
Cohort Studies
0302 clinical medicine
Focal Adhesion Protein-Tyrosine Kinases/metabolism
Diabetic Nephropathies
Cells
Cultured
Integrin beta1/metabolism
Kinase
Podocytes
Integrin beta1
Motility
Cell biology
medicine.anatomical_structure
FoxO1
030220 oncology & carcinogenesis
Adhesion
Diabetes Mellitus
Type 2/genetics
Signal Transduction
Podocytes/metabolism
Kidney Glomerulus/metabolism
Diabetic Nephropathies/genetics
Biology
Endothelial Cells/metabolism
Article
03 medical and health sciences
Internal Medicine
medicine
Humans
Viability assay
PI3K/AKT/mTOR pathway
FAK
β1-integrin
Endothelial Cells
IGFBP-1
medicine.disease
Insulin-Like Growth Factor Binding Protein 1
Kidney/metabolism
030104 developmental biology
Diabetes Mellitus
Type 2
Focal Adhesion Protein-Tyrosine Kinases
Glomerulus
Signal Transduction/genetics
Insulin-Like Growth Factor Binding Protein 1/genetics
Zdroj: Diabetologia
Lay, A C, Hale, L J, Stowell-Connolly, H, Pope, R J P, Nair, V, Ju, W, Marquez, E, Rollason, R, Hurcombe, J A, Hayes, B, Roberts, T, Gillam, L, Allington, J, Nelson, R G, Kretzler, M, Holly, J M P, Perks, C M, McArdle, C A, Welsh, G I & Coward, R J M 2021, ' IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes ', Diabetologia, vol. 64, no. 7, pp. 1690-1702 . https://doi.org/10.1007/s00125-021-05427-1
ISSN: 0012-186X
DOI: 10.1007/s00125-021-05427-1
Popis: 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
Databáze: OpenAIRE
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