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.

中文翻译：

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芳基烃受体和半胱氨酸氧化还原动力学是肾皮质慢性间歇性缺氧的（Mal）适应机制

我们假设肾皮质中芳烃受体 (AhR) 和半胱氨酸相关硫醇组之间的相互作用是对慢性间歇性缺氧 (CIH) 的 (mal) 适应机制的基础，促进动脉高血压 (HTN)。使用 CIH-HTN 大鼠模型，我们研究了短期（1 天和 7 天）、中期（14 天和 21 天，HTN 前）和长期间歇性缺氧 (IH)（高达60 天，在 Cyp1a1 蛋白水平（AhR 激活的敏感标志）和半胱氨酸相关硫醇池上建立 HTN。我们发现急性和慢性 IH 对 Cyp1a1 和硫醇组有相反的影响。虽然短期 IH 降低了 Cyp1a1 并增加了蛋白质-S-硫醇化，长期 IH 增加 Cyp1a1 和游离氧化半胱氨酸。此外，将胱氨酸（而非半胱氨酸）体外给药至人内皮细胞可增加Cyp1a1表达，支持胱氨酸作为推定的 AhR 激活剂。该研究支持 Cyp1a1 作为阻塞性睡眠呼吸暂停 (OSA) 严重程度的生物标志物，并将半胱氨酸氧化池作为 OSA-HTN 的风险指标。这项工作有助于更好地理解由该模型模拟的 OSA-HTN 表型的潜在机制，这符合 OSA 中的精准医学挑战。