Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex

Abstract

We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.

Gender Differences in the Context of Obstructive Sleep Apnea and Metabolic Diseases

“…It has been described that muscle sympathetic activity and blood and urine catecholamine levels are higher in sleep apneic patients in comparison to age- and BMI-matched controls (both norepinephrine and epinephrine) (Narkiewicz and Somers, 1999 ; Dempsey et al, 2010 ). Additionally, several studies show that chronic intermittent hypoxia can induce hypertension and sympathetic activation, both in laboratory animals (Fletcher et al, 1992 ; Greenberg et al, 1999 ; Zoccal et al, 2008 ; Marcus et al, 2010 ; Aller et al, 2020 ; Ferreira et al, 2020 ; Correia et al, 2021 ) and in humans (Tamisier et al, 2011 ). However, since sleep interruption and arousals, characteristic of the OSA condition, can also cause hypertension, some studies suggest that recurrent sleep disturbance also contributes to sympathetic overactivity and catecholamines levels increase in OSA patients, remaining to understand the specific impact of each parameter (Faraut et al, 2012 ; Chouchou et al, 2013 ; Taylor et al, 2016 ) on arterial pressure.…”

Pharmacological blockage of the AHR-CYP1A1 axis: a call for in vivo evidence

“…Among the endogenous ligands, some ultraviolet photoproducts of tryptophan have been described as the 6-formylindolo [3,2-b]carbazole (FICZ); the indigoids indigo and indirubin; the kynurenine (Kyn) and its metabolites including kynurenic acid; the metabolites of arachidonic acid like lipoxin 4A, prostaglandin G2, and hydroxyeicosatetraenoic acid; and cystine [7] and the tetrapyrroles derived from heme, biliverdin, and bilirubin (reviewed by [8,9]). This vast ligand promiscuity converges in the fact that according to the ligand, AHR might be activated in a diverse manner and in a cell-and tissue-dependent way [3,5].…”

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

“…Molecules 2022, 27, x FOR PEER REVIEW 2 of 2 and cysteine persulfide (CysSSH) [7], all of them playing an essential role in kidne bioenergetics, function and blood pressure regulation (reviewed in References [8,9]). Similar to other aminothiols, the total cysteine availability in fluids and tissues is sum of three fractions: a free reduced (CysSH) and two oxidized corresponding to the fre oxidized (CysSSX, cysteine disulfides, mainly cystine) and the protein-bound (CysSSP b S-cysteinylation of cysteine residues) fractions [10,11]. Cysteine is mostly present i extracellular fluids, wherein it is predominantly found in its oxidized forms [12][13][14].…”

“…The cysteine redox equilibrium also contributes to adaptive responses to physiologic and non-physiologic stimuli [10,11,65]. For instance, the redox equilibrium of Cys/CysSS is crucial for endothelial cells [11,66] and the control of vascular health [67], as cysteine and cystine elicit different responses [11,65]. This redox pair equilibrium changes in the kidney upon hypertensive stimuli [10,11] and is independent of the GSH/GSSG ratio.…”

“…For instance, the redox equilibrium of Cys/CysSS is crucial for endothelial cells [11,66] and the control of vascular health [67], as cysteine and cystine elicit different responses [11,65]. This redox pair equilibrium changes in the kidney upon hypertensive stimuli [10,11] and is independent of the GSH/GSSG ratio. Cysteine redox cycling has important consequences in DNA repair, cell proliferation, apoptosis, ER stress and inflammatory response [68], the functional inactivation of enzymes, activation of the unfolded protein response [69] and antioxidant response elements [23,70,71].…”