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Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury

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 dep...

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Main Authors: Zhou, Luping (Author) , Pereiro, Marc Torres (Author) , Li, Yanqun (Author) , Derigs, Marcus (Author) , Kuenne, Carsten (Author) , Hielscher, Thomas (Author) , Huang, Wei (Author) , Kränzlin, Bettina (Author) , Tian, Gang (Author) , Kobayashi, Kazuhiro (Author) , Lu, Gia-Hue Natalie (Author) , Roedl, Kevin (Author) , Schmidt, Claudia (Author) , Günther, Stefan (Author) , Looso, Mario (Author) , Huber, Johannes (Author) , Xu, Yong (Author) , Wiech, Thorsten (Author) , Sperhake, Jan-Peter (Author) , Wichmann, Dominic (Author) , Gröne, Hermann-Josef (Author) , Worzfeld, Thomas (Author)
Format: Article (Journal)
Language:English
Published: Oct 2024
In: Science translational medicine
Year: 2024, Volume: 16, Issue: 767, Pages: 1-16
ISSN:1946-6242
DOI:10.1126/scitranslmed.adk5005
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1126/scitranslmed.adk5005
Verlag, kostenfrei, Volltext: https://www.science.org/doi/10.1126/scitranslmed.adk5005
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Author Notes:Luping Zhou, Marc Torres Pereiro, Yanqun Li, Marcus Derigs, Carsten Kuenne, Thomas Hielscher, Wei Huang, Bettina Kränzlin, Gang Tian, Kazuhiro Kobayashi, Gia-Hue Natalie Lu, Kevin Roedl, Claudia Schmidt, Stefan Günther, Mario Looso, Johannes Huber, Yong Xu, Thorsten Wiech, Jan-Peter Sperhake, Dominic Wichmann, Hermann-Josef Gröne, Thomas Worzfeld
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Summary: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.
Item Description:Online veröffentlicht: 2. Oktober 2024
Gesehen am 12.05.2025
Physical Description:Online Resource
ISSN:1946-6242
DOI:10.1126/scitranslmed.adk5005

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