Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid–induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.

中文翻译：

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糖皮质激素可诱导适应不良的上皮应激反应，从而加重急性肾损伤


急性肾损伤 （AKI） 是一种常见且具有挑战性的临床疾病，与高发病率和死亡率相关，是 COVID-19 危重患者的常见并发症。在 AKI 中，肾小管上皮细胞 （TECs） 是损伤的主要部位，从 AKI 中恢复取决于 TEC 可塑性。然而，AKI 中 TECs 适应和适应不良的分子机制在很大程度上仍不清楚。在这里，我们对 COVID-19 患者的尸检队列的研究提供了证据，证明肌红蛋白对 TEC 的损伤（作为横纹肌溶解的结果）是严重 COVID-19 中 AKI 的主要病理生理机制。对人肾活检、肌红蛋白尿和庆大霉素诱导的 AKI 小鼠模型以及小鼠肾小管的分析表明，TEC 损伤导致内源性糖皮质激素激活糖皮质激素受体，从而加重了肾小管损伤。内源性糖皮质激素对受伤 TEC 的有害影响因临床广泛使用的合成糖皮质激素地塞米松的给药而加剧，正如肌红蛋白尿酸和叶酸诱导的 AKI、人和小鼠肾小管以及人肾切片培养物的小鼠模型中的实验所表明的那样。从机制上讲，对 AKI、小鼠肾小管和人肾切片培养物小鼠模型的研究表明，受伤 TEC 中的糖皮质激素受体信号传导编排了适应不良的转录程序，以阻碍 DNA 修复，放大损伤诱导的 DNA 双链断裂形成，并抑制 mTOR 活性和线粒体生物能量学。本研究确定糖皮质激素受体激活是上皮适应不良的一种机制，这对 AKI 具有重要的功能意义。