Yoshida Yuya, Nishikawa Naoki, Fukuoka Kohei, Tsuruta Akito, Otsuki Kaita, Fukuda Taiki, Terada Yuma, Tanihara Tomohito, Kumamoto Taisei, Tsukamoto Ryotaro, Nishi Takumi, Oyama Kosuke, Hamamura Kengo, Mayanagi Kouta, Koyanagi Satoru, Ohdo Shigehiro, Matsunaga Naoya
Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Int J Mol Sci. 2024 Dec 3;25(23):13009. doi: 10.3390/ijms252313009.
Defects in Aryl hydrocarbon receptor nuclear translocator-like 1 (ARNTL), a central component of the circadian clock mechanism, may promote or inhibit the induction of inflammation by monocytes/macrophages, with varying effects on different diseases. However, ARNTL's role in monocytes/macrophages under chronic kidney disease (CKD), which presents with systemic inflammation, is unclear. Here, we report that the expression of in monocytes promoted CKD-induced cardiac damage. The expression of G-protein-coupled receptor 68 (GPR68), which exacerbates CKD-induced cardiac disease, was regulated by ARNTL. Under CKD conditions, GPR68 expression was elevated via ARNTL, particularly in the presence of PU.1, a transcription factor specific to monocytes and macrophages. In CKD mouse models lacking monocyte-specific ARNTL, GPR68 expression in monocytes was reduced, leading to decreased cardiac damage and fibrosis despite no improvement in renal excretory capacity or renal fibrosis and increased angiotensin II production. The loss of ARNTL did not affect the expression of marker molecules, indicating the origin or differentiation of cardiac macrophages, but affected GPR68 expression only in cardiac macrophages derived from mature monocytes, highlighting the significance of the interplay between GPR68 and ARNTL in monocytes/macrophages and its influence on cardiac pathology. Understanding this complex relationship between circadian clock mechanisms and disease could help uncover novel therapeutic strategies.
芳烃受体核转运蛋白样1（ARNTL）是生物钟机制的核心组成部分，其缺陷可能促进或抑制单核细胞/巨噬细胞诱导的炎症反应，对不同疾病有不同影响。然而，ARNTL在伴有全身炎症的慢性肾脏病（CKD）中单核细胞/巨噬细胞里的作用尚不清楚。在此，我们报告单核细胞中ARNTL的表达促进了CKD诱导的心脏损伤。加剧CKD诱导的心脏疾病的G蛋白偶联受体68（GPR68）的表达受ARNTL调控。在CKD条件下，GPR68的表达通过ARNTL升高，特别是在存在PU.1（一种单核细胞和巨噬细胞特有的转录因子）的情况下。在缺乏单核细胞特异性ARNTL的CKD小鼠模型中，单核细胞中GPR68的表达降低，尽管肾排泄能力、肾纤维化没有改善且血管紧张素II生成增加，但心脏损伤和纤维化减少。ARNTL的缺失不影响标记分子的表达，标记分子表明心脏巨噬细胞的起源或分化，但仅影响源自成熟单核细胞的心脏巨噬细胞中GPR68的表达，突出了GPR68与ARNTL在单核细胞/巨噬细胞中的相互作用及其对心脏病理学影响的重要性。了解生物钟机制与疾病之间的这种复杂关系有助于揭示新的治疗策略。
