Aryl Hydrocarbon Receptor Inhibition Restores Indoxyl Sulfate-Mediated Endothelial Dysfunction in Rat Aortic Rings.

Cindy Nguyen,Andrew R Kompa,Amanda J Edgley,Darren J Kelly

doi:10.3390/toxins14020100

Cindy Nguyen, Andrew R Kompa + Show 2 more

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https://doi.org/10.3390/toxins14020100

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Journal: Toxins	Publication Date: Jan 26, 2022
Citations: 14	License type: CC BY 4.0

Affiliation: St Vincent's Hospital, University of Melbourne

Abstract

The uremic toxin indoxyl sulfate (IS), elevated in chronic kidney disease (CKD), is known to contribute towards progressive cardiovascular disease. IS activates the aryl hydrocarbon receptor (AhR) mediating oxidative stress and endothelial dysfunction via activation of the CYP1A1 pathway. The present study examines AhR inhibition with the antagonist, CH223191, on IS-mediated impairment of vascular endothelial function and disruption of redox balance. The acute effects of IS on endothelium-dependent relaxation were assessed in aortic rings from Sprague Dawley rats exposed to the following conditions: (1) control; (2) IS (300 μM); (3) IS + CH223191 (1 μM); (4) IS + CH223191 (10 μM). Thereafter, tissues were assessed for changes in expression of redox markers. IS reduced the maximum level of endothelium-dependent relaxation (Rmax) by 42% (p < 0.001) compared to control, this was restored in the presence of increasing concentrations of CH223191 (p < 0.05). Rings exposed to IS increased expression of CYP1A1, nitro-tyrosine, NADPH oxidase 4 (NOX4), superoxide, and reduced eNOS expression (p < 0.05). CH223191 (10 μM) restored expression of these markers back to control levels (p < 0.05). These findings demonstrate the adverse impact of IS-mediated AhR activation on the vascular endothelium, where oxidative stress may play a critical role in inducing endothelial dysfunction in the vasculature of the heart and kidneys. AhR inhibition could provide an exciting novel therapy for CVD in the CKD setting.

Highlights

chronic kidney disease (CKD) affects 10% of the global population, impacting health systems and placing a heavy economic and productivity burden on countries worldwide [1,2]
Increased cytochrome P450 1A1 (CYP1A1) and reactive oxygen species (ROS) production induced by aryl hydrocarbon receptor (AhR) activation plays an integral role in the impairment of endothelium-dependent vasodilatation [24,25]
The results of the present study suggest that blockade of the AhR with CH223191 alleviated indoxyl sulfate (IS)-mediated prooxidative CYP1A1 gene expression and ROS production in the aorta and preserved endothelial nitric oxide synthase (eNOS) expression and the endothelium-dependent vasodilator response to ACh

Summary

Introduction

CKD affects 10% of the global population, impacting health systems and placing a heavy economic and productivity burden on countries worldwide [1,2]. The risk of cardiovascular disease (CVD) is increased in patients with chronic kidney disease (CKD) [3]. In these patients, the accumulation of non-dialyzable circulating proteinbound uremic toxins (PBUTS) such as the indoxyl sulfate (IS) demonstrate an increased CVD mortality [4], and predict adverse cardiovascular events in patients with chronic heart failure [5]. Other studies have observed that narrowing of the microvasculature in patients with CKD is associated with decreased estimated glomerular filtration rate [9]. Animal studies have reported that IS, whether increased in a model CKD or administered exogenously, contributes to impaired endothelium-dependent vasorelaxation [10,11]

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