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

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.