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

TY - JOUR

T1 - Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury

AU - Zhou, Luping

AU - Pereiro, Marc Torres

AU - Li, Yanqun

AU - Derigs, Marcus

AU - Kuenne, Carsten

AU - Hielscher, Thomas

AU - Huang, Wei

AU - Kränzlin, Bettina

AU - Tian, Gang

AU - Kobayashi, Kazuhiro

AU - Lu, Gia-Hue Natalie

AU - Roedl, Kevin

AU - Schmidt, Claudia

AU - Günther, Stefan

AU - Looso, Mario

AU - Huber, Johannes

AU - Xu, Yong

AU - Wiech, Thorsten

AU - Sperhake, Jan-Peter

AU - Wichmann, Dominic

AU - Gröne, Hermann-Josef

AU - Worzfeld, Thomas

PY - 2024/10/2

Y1 - 2024/10/2

N2 - 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.

AB - 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.

KW - Animals

KW - Acute Kidney Injury/metabolism

KW - Humans

KW - Glucocorticoids/adverse effects

KW - COVID-19/complications

KW - Mice

KW - Epithelial Cells/metabolism

KW - Receptors, Glucocorticoid/metabolism

KW - Disease Models, Animal

KW - Male

KW - Kidney Tubules/pathology

KW - Myoglobin/metabolism

KW - Dexamethasone/pharmacology

KW - Stress, Physiological/drug effects

KW - SARS-CoV-2

KW - Mice, Inbred C57BL

KW - Female

U2 - 10.1126/scitranslmed.adk5005

DO - 10.1126/scitranslmed.adk5005

M3 - SCORING: Journal article

C2 - 39356748

VL - 16

SP - eadk5005

JO - SCI TRANSL MED

JF - SCI TRANSL MED

SN - 1946-6234

IS - 767

ER -