IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes.
Biopsy
Cells, Cultured
Cohort Studies
Diabetes Mellitus, Type 2
/ genetics
Diabetic Nephropathies
/ genetics
Endothelial Cells
/ metabolism
Focal Adhesion Protein-Tyrosine Kinases
/ metabolism
Humans
Insulin-Like Growth Factor Binding Protein 1
/ genetics
Integrin beta1
/ metabolism
Kidney
/ metabolism
Kidney Glomerulus
/ metabolism
Podocytes
/ metabolism
Signal Transduction
/ genetics
Adhesion
Diabetic nephropathy
FAK
Fkhr
FoxO1
Glomerulus
IGFBP-1
Motility
Podocyte
β1-integrin
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
14
05
2020
accepted:
14
01
2021
pubmed:
25
3
2021
medline:
11
3
2022
entrez:
24
3
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 33758952
doi: 10.1007/s00125-021-05427-1
pii: 10.1007/s00125-021-05427-1
pmc: PMC8187213
doi:
Substances chimiques
IGFBP1 protein, human
0
Insulin-Like Growth Factor Binding Protein 1
0
Integrin beta1
0
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1690-1702Subventions
Organisme : Medical Research Council
ID : MR/K010492/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T002263/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK081943
Pays : United States
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