Angiotensin II induced oxidative stress-mediated upregulation of sodium-glucose cotransporters 1 and 2 (SGLTs) expression in cultured coronary artery endothelial cells

[Speaker] Valerie B Schini-Kerth:1
[Co-author] Sin-Hee Park:1, Eugenia Belcastro:1, Hira Hasan:1, Cyril Auger:1
1:INSERM, UMR 1260, Regenerative Nanomedicine, Faculty of Pharmacy, University of Strasbourg, France

Background and Aim: Endothelial dysfunction is a major hallmark of cardiovascular diseases including diabetes. The fact that inhibition of the angiotensin system improved endothelial dysfunction in experimental models of diabetes, indicates a determinant role of angiotensin II (Ang II). Glucose uptake across cell membrane involves glucose transporters including the sodium-glucose cotransporters (SGLTs) promoting oxidative stress and glucotoxicity. This study assessed the possibility that Ang II induces the expression of SGLT1 and SGLT2 in endothelial cells (ECs) leading to endothelial dysfunction.
Methods: ECs were isolated from porcine coronary arteries using collagenase, cultured and used at passage 1. The level of target protein expression was investigated by Western blot analysis and immunocytochemical staining, and oxidative stress using dihydroethidium staining.
Results: Control ECs expressed low levels of SGLT1 and SGLT2 proteins. Exposure of ECs to Ang II caused a time-dependent increase in the protein level of SGLT1 and SGLT2. The stimulatory effect of Ang II at 24 h was concentration-dependent with a significant increase at concentrations greater than 10 nM. Ang II increased the SGLT1 and SGLT2 fluorescence signals by about 2.8 and 2.1 fold, respectively. An upregulation of SGLT1 and SGLT2 fluorescence signals was also observed in response to hydrogen peroxide (0.1 mM). The stimulatory effect of Ang II was associated with an increased level of oxidative stress in ECs and an upregulation of VCAM-1. The Ang II-induced upregulation of SGLT1, SGLT2 and VCAM-1 was inhibited by the NADPH oxidase inhibitor VAS-2870 and by inhibitors of the mitochondrial respiration chain.
Conclusions: The present findings indicate that Ang II upregulates the expression of SGLT1 and SGLT2 protein levels in ECs most likely by triggering NADPH oxidase- and mitochondrial respiratory chain-derived oxidative stress. They further raise the possibility that SGLT1 and SGLT2 might contribute to enhance endothelial glucotoxicity thereby promoting endothelial dysfunction.

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