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Aryl Hydrocarbon Receptor Inhibition Restores Indoxyl Sulfate-Mediated Endothelial Dysfunction in Rat Aortic Rings.
Nguyen, Cindy; Edgley, Amanda J; Kelly, Darren J; Kompa, Andrew R.
Afiliación
  • Nguyen C; Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy 3065, Australia.
  • Edgley AJ; Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy 3065, Australia.
  • Kelly DJ; Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy 3065, Australia.
  • Kompa AR; Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy 3065, Australia.
Toxins (Basel) ; 14(2)2022 01 26.
Article en En | MEDLINE | ID: mdl-35202128
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aorta Torácica / Pirazoles / Compuestos Azo / Endotelio Vascular / Receptores de Hidrocarburo de Aril / Indicán Límite: Animals Idioma: En Revista: Toxins (Basel) Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aorta Torácica / Pirazoles / Compuestos Azo / Endotelio Vascular / Receptores de Hidrocarburo de Aril / Indicán Límite: Animals Idioma: En Revista: Toxins (Basel) Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Suiza