Alcohol abuse is one of the major public health problems in the world and is associated with various health conditions. However, little is known about the effect of alcohol consumption on acute kidney injury (AKI). In this study, we demonstrate that chronic and binge alcohol feeding with a Lieber-DeCarli diet containing 5 % ethanol for 10 days, followed by a single dose of 31.5 % ethanol by gavage, aggravated AKI after ischemia-reperfusion injury (IRI) in female, but not in male, mice. Kidney dysfunction, histopathology and tubular cell apoptosis were more severe in EtOH-fed female mice after IRI, compared to pair-fed controls. RNA sequencing and experimental validation uncovered that activation of integrin β1 and its downstream c-Jun NH2-terminal kinase (JNK) aggravated AKI in EtOH-fed mice. Knockdown of integrin β1 inhibited JNK phosphorylation and alleviated AKI in EtOH-fed mice, whereas activation of integrin β1 by agonist antibody increased JNK phosphorylation, worsened renal histological injury and tubular cell apoptosis, and aggravated kidney dysfunction. In vitro, activation of integrin β1 increased JNK phosphorylation and induced tubular epithelial cell apoptosis. The detrimental effect of EtOH feeding was primarily mediated by acetaldehyde, as its levels were increased in the blood, liver and kidney of female mice fed with ethanol. Acetaldehyde per se activated integrin β1/JNK signaling and induced tubular cell apoptosis in vitro. These findings suggest that alcohol consumption increases vulnerability to AKI in female mice, which is probably mediated by acetaldehyde/integrin β1/JNK signaling cascade.

中文翻译：

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长期饮酒通过整合素 β1/JNK 信号转导加重急性肾损伤


酗酒是世界上主要的公共卫生问题之一，与各种健康状况有关。然而，关于饮酒对急性肾损伤 （AKI） 的影响知之甚少。在这项研究中，我们证明，用含有 5% 乙醇的 Lieber-DeCarli 饮食进行慢性和酗酒喂养 10 天，然后通过管饲法单剂量 31.5% 乙醇，在雌性缺血再灌注损伤 （IRI） 后加重 AKI，但在雄性小鼠中则没有。与配对喂养的对照相比，IRI 后 EtOH 喂养的雌性小鼠的肾功能障碍、组织病理学和肾小管细胞凋亡更为严重。RNA 测序和实验验证发现，整合素 β 1 及其下游 c-Jun NH2 末端激酶 （JNK） 的激活会加重 EtOH 喂养小鼠的 AKI。敲除整合素 β1 抑制 JNK 磷酸化并减轻 EtOH 喂养小鼠的 AKI，而激动剂抗体激活整合素 β 1 会增加 JNK 磷酸化，恶化肾组织学损伤和肾小管细胞凋亡，并加重肾功能障碍。在体外，整合素 β 1 的激活增加了 JNK 磷酸化并诱导肾小管上皮细胞凋亡。EtOH 喂养的有害作用主要由乙醛介导，因为乙醇喂养的雌性小鼠的血液、肝脏和肾脏中的乙醛水平升高。乙醛本身在体外激活整合素 β1/JNK 信号传导并诱导肾小管细胞凋亡。这些发现表明，饮酒会增加雌性小鼠对 AKI 的易感性，这可能是由乙醛/整合素 β1/JNK 信号级联介导的。