Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells.

Marie-Hélène Antoine,Tatiana Yankep,Jean-Marie Colet,Joëlle Nortier,Vanessa Tagliatti,Souhaila Mahria,Cécile Husson

doi:10.3390/toxins14020132

Marie-Hélène Antoine, Tatiana Yankep + Show 5 more

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https://doi.org/10.3390/toxins14020132

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Journal: Toxins	Publication Date: Feb 10, 2022
Citations: 2	License type: CC BY 4.0

Affiliation: Université Libre de Bruxelles, University of Mons

Abstract

Aristolochic acids (AAs) are powerful nephrotoxins that cause severe tubulointerstitial fibrosis. The biopsy-proven peritubular capillary rarefaction may worsen the progression of renal lesions via tissue hypoxia. As we previously observed the overproduction of reactive oxygen species (ROS) by cultured endothelial cells exposed to AA, we here investigated in vitro AA-induced metabolic changes by 1H-NMR spectroscopy on intracellular medium and cell extracts. We also tested the effects of nebivolol (NEB), a β-blocker agent exhibiting antioxidant properties. After 24 h of AA exposure, significantly reduced cell viability and intracellular ROS overproduction were observed in EAhy926 cells; both effects were counteracted by NEB pretreatment. After 48 h of exposure to AA, the most prominent metabolite changes were significant decreases in arginine, glutamate, glutamine and glutathione levels, along with a significant increase in the aspartate, glycerophosphocholine and UDP-N-acetylglucosamine contents. NEB pretreatment slightly inhibited the changes in glutathione and glycerophosphocholine. In the supernatants from exposed cells, a decrease in lactate and glutamate levels, together with an increase in glucose concentration, was found. The AA-induced reduction in glutamate was significantly inhibited by NEB. These findings confirm the involvement of oxidative stress in AA toxicity for endothelial cells and the potential benefit of NEB in preventing endothelial injury.

Highlights

Aristolochic acids (AAs) are active compounds contained in medicinal plants from the Aristolochia and Asarum species
We previously demonstrated that AA produced oxidative stress in endothelial cells, which may contribute to endothelial dysfunction and cell death [10]
The results of this study show that pretreatment with NEB significantly restored the cell viability and cell morphology and reduced the reactive oxygen species (ROS) production induced by AA in endothelial cells

Summary

Introduction

Aristolochic acids (AAs) are active compounds contained in medicinal plants from the Aristolochia and Asarum species. The onset and progression of renal fibrosis are experimentally characterized by an acute phase (i.e., tubular necrosis of the S3 segment of the proximal tubule reflecting acute kidney injury (AKI)) followed by marked tubular atrophy and interstitial fibrosis leading to end-stage kidney disease [3]. Beside these well-established histologic features of AAN, marked capillary rarefaction has been observed [4,5]. Yang et al demonstrated that the protein expression of endothelial nitric oxide synthase (eNOS) was reduced by AAs in a mouse model of AAN [13]. Restoring the bioavailability of NO by reducing oxidative stress has been shown to improve renal function in AA-treated mice [14]

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