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000293859 041__ $$aEnglish
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000293859 1001_ $$00000-0003-1065-6604$$aZhou, Luping$$b0
000293859 245__ $$aGlucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury.
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000293859 520__ $$aAcute 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.
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000293859 650_7 $$2NLM Chemicals$$aGlucocorticoids
000293859 650_7 $$2NLM Chemicals$$aReceptors, Glucocorticoid
000293859 650_7 $$2NLM Chemicals$$aMyoglobin
000293859 650_7 $$07S5I7G3JQL$$2NLM Chemicals$$aDexamethasone
000293859 650_2 $$2MeSH$$aAnimals
000293859 650_2 $$2MeSH$$aAcute Kidney Injury: metabolism
000293859 650_2 $$2MeSH$$aAcute Kidney Injury: pathology
000293859 650_2 $$2MeSH$$aHumans
000293859 650_2 $$2MeSH$$aGlucocorticoids: adverse effects
000293859 650_2 $$2MeSH$$aGlucocorticoids: pharmacology
000293859 650_2 $$2MeSH$$aCOVID-19: complications
000293859 650_2 $$2MeSH$$aCOVID-19: metabolism
000293859 650_2 $$2MeSH$$aMice
000293859 650_2 $$2MeSH$$aEpithelial Cells: metabolism
000293859 650_2 $$2MeSH$$aEpithelial Cells: drug effects
000293859 650_2 $$2MeSH$$aEpithelial Cells: pathology
000293859 650_2 $$2MeSH$$aReceptors, Glucocorticoid: metabolism
000293859 650_2 $$2MeSH$$aDisease Models, Animal
000293859 650_2 $$2MeSH$$aMale
000293859 650_2 $$2MeSH$$aKidney Tubules: pathology
000293859 650_2 $$2MeSH$$aKidney Tubules: metabolism
000293859 650_2 $$2MeSH$$aKidney Tubules: drug effects
000293859 650_2 $$2MeSH$$aMyoglobin: metabolism
000293859 650_2 $$2MeSH$$aDexamethasone: pharmacology
000293859 650_2 $$2MeSH$$aDexamethasone: adverse effects
000293859 650_2 $$2MeSH$$aStress, Physiological: drug effects
000293859 650_2 $$2MeSH$$aSARS-CoV-2
000293859 650_2 $$2MeSH$$aMice, Inbred C57BL
000293859 650_2 $$2MeSH$$aFemale
000293859 7001_ $$00000-0003-3359-7715$$aPereiro, Marc Torres$$b1
000293859 7001_ $$00009-0008-8470-676X$$aLi, Yanqun$$b2
000293859 7001_ $$aDerigs, Marcus$$b3
000293859 7001_ $$00000-0001-8013-5906$$aKuenne, Carsten$$b4
000293859 7001_ $$0P:(DE-He78)743a4a82daab55306a2c88b9f6bf8c2f$$aHielscher, Thomas$$b5$$udkfz
000293859 7001_ $$aHuang, Wei$$b6
000293859 7001_ $$00000-0003-1533-4057$$aKränzlin, Bettina$$b7
000293859 7001_ $$00000-0002-4116-3215$$aTian, Gang$$b8
000293859 7001_ $$00000-0002-5390-8966$$aKobayashi, Kazuhiro$$b9
000293859 7001_ $$00009-0008-5096-1594$$aLu, Gia-Hue Natalie$$b10
000293859 7001_ $$00000-0002-0721-9027$$aRoedl, Kevin$$b11
000293859 7001_ $$0P:(DE-He78)2a599a43bd0b5910c80edb288d8da3e5$$aSchmidt, Claudia$$b12$$udkfz
000293859 7001_ $$00000-0002-5594-4549$$aGünther, Stefan$$b13
000293859 7001_ $$00000-0003-1495-9530$$aLooso, Mario$$b14
000293859 7001_ $$00000-0001-7243-8958$$aHuber, Johannes$$b15
000293859 7001_ $$00000-0002-9534-6252$$aXu, Yong$$b16
000293859 7001_ $$00000-0003-4053-1474$$aWiech, Thorsten$$b17
000293859 7001_ $$aSperhake, Jan-Peter$$b18
000293859 7001_ $$aWichmann, Dominic$$b19
000293859 7001_ $$aGröne, Hermann-Josef$$b20
000293859 7001_ $$00000-0003-3908-403X$$aWorzfeld, Thomas$$b21
000293859 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.adk5005$$gVol. 16, no. 767, p. eadk5005$$n767$$peadk5005$$tScience translational medicine$$v16$$x1946-6234$$y2024
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