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. and Coward, Richard J. M. (2018) Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress. Scientific Reports, 8 (1). p. 3902. ISSN 2045-2322

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Official URL: https://doi.org/10.1038/s41598-018-22233-9

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.

Item Type: Article
Subjects: A400 Clinical Dentistry
B200 Pharmacology, Toxicology and Pharmacy
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 28 May 2020 13:20
Last Modified: 28 May 2020 13:30
URI: http://nrl.northumbria.ac.uk/id/eprint/43264

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