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Sci Rep. 2018 Mar 2;8(1):3902. doi: 10.1038/s41598-018-22233-9.

Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress.

Author information

1
Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
2
Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge, CB4 0PZ, UK.
3
Laboratories for Integrative Neuroscience and Endocrinology, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
4
Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. Richard.Coward@bristol.ac.uk.

Abstract

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.

PMID:
29500363
PMCID:
PMC5834602
DOI:
10.1038/s41598-018-22233-9
[Indexed for MEDLINE]
Free PMC Article

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