First evidence of aryl hydrocarbon receptor as a druggable target in hypertension induced by chronic intermittent hypoxia

Nuno R. Coelho, Céline Tomkiewicz, M. João Correia, Clara Gonçalves-Dias, Robert Barouki, Sofia A. Pereira, Xavier Coumoul, Emília C. Monteiro

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1 Citation (Scopus)

Abstract

Background and Purpose: Obstructive sleep apnea (OSA) is associated to a high prevalence of resistant arterial hypertension (HTN) justifying the research on novel targets. Chronic intermittent hypoxia (CIH) is a key feature in the development of OSA comorbidities, including HTN. Experimental Approach: We used a rat model of CIH-induced HTN to disclose the hypothesis that the aryl hydrocarbon receptor (AHR) is activated by CIH once it shares the same binding partner of HIF-1α and promotes pro-oxidant, pro-inflammatory (NF-kB) and pro-fibrotic events in common with CIH. Key Results: Upon established hypertension (21 days exposure to CIH), we observed an increase in Cyp1a1 mRNA in kidney cortex (6-fold), kidney medulla (3-fold) and liver (3-fold), but not in other tissues. Increased renal expression of Ahr and markers of inflammation (Rela), epithelial to mesenchymal transition markers, the rate-controlling step of gluconeogenesis, Pepck1, and members of HIF-pathway, namely, Hif3a were also observed. Daily administration (14 days) of AHR antagonist, CH-223191 (5 mg.kg-1.day-1, gavage), simultaneously to CIH prevented the increase in systolic blood pressure (SBP) by 53 ± 12% and in diastolic blood pressure (DBP) by 44 ± 16%. Moreover, its administration (14 days) upon already established HTN reversed the increase in SBP by 52 ± 12%. Conclusion and Implications: CIH caused an activation of AHR signaling particularly in the kidney and its pharmacological blockade had a significant impact reverting already established HTN. This first evidence inspires innovative research opportunities for the understanding and treatment of this particular type of HTN.

Original languageEnglish
Article number104869
JournalPharmacological Research
Volume159
DOIs
Publication statusPublished - Sep 2020

Keywords

  • AHR
  • blood pressure.
  • CH-223191
  • CYP1A1
  • kidney
  • Secondary hypertension

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