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27.07.2016 | Nephrology - Original Paper

Activation of general control nonderepressible 2 kinase protects human glomerular endothelial cells from harmful high-glucose-induced molecular pathways

verfasst von: Theodoros Eleftheriadis, Konstantina Tsogka, Georgios Pissas, Georgia Antoniadi, Vassilios Liakopoulos, Ioannis Stefanidis

Erschienen in: International Urology and Nephrology | Ausgabe 10/2016

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Abstract

Purpose

Considering the referred beneficial effects of protein restriction on diabetic nephropathy (DN) and the role of renal endothelium in its pathogenesis, we evaluated the effect of general control nonderepressible 2 (GCN2) kinase activation, a sensor of amino acid deprivation, on known detrimental molecular pathways in primary human glomerular endothelial cells (GEnC).

Methods

GEnC were cultured under normal or high-glucose conditions in the presence or not of the GCN2 kinase activator, tryptophanol. Glucose transporter 1 (GLUT1) expression was assessed by western blotting and reactive oxygen species (ROS) using a fluorogenic probe. Activities of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and protein kinase C (PKC) were assessed by commercial activity assays, sorbitol colorimetrically, methylglyoxal by ELISA and O-linked β-N-acetyl glucosamine (O-GlcNAc)-modified proteins by western blotting.

Results

High glucose induced GLUT1 expression, increased ROS and inhibited GAPDH. Also it increased the polyol pathway product sorbitol, PKC activity, the level of the O-GlcNAc-modified proteins that produced by the hexosamine pathway and the advanced glycation endproducts’ precursor methylglyoxal. Co-treatment of GEnC with tryptophanol restored the above high-glucose-induced alterations.

Conclusions

Activation of GCN2 kinase protects GEnC from high-glucose-induced harmful molecular pathways. By inhibiting concurrently many pathways involved in DN pathogenesis, GCN2 kinase may serve as a pharmaceutical target for the treatment of DN.

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Titel: Activation of general control nonderepressible 2 kinase protects human glomerular endothelial cells from harmful high-glucose-induced molecular pathways
verfasst von: Theodoros Eleftheriadis
Konstantina Tsogka
Georgios Pissas
Georgia Antoniadi
Vassilios Liakopoulos
Ioannis Stefanidis
Publikationsdatum: 27.07.2016
Verlag: Springer Netherlands
Erschienen in: International Urology and Nephrology / Ausgabe 10/2016
Print ISSN: 0301-1623
Elektronische ISSN: 1573-2584
DOI: https://doi.org/10.1007/s11255-016-1377-x

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