Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury
Standard
Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury. / Zhou, Luping; Pereiro, Marc Torres; Li, Yanqun; Derigs, Marcus; Kuenne, Carsten; Hielscher, Thomas; Huang, Wei; Kränzlin, Bettina; Tian, Gang; Kobayashi, Kazuhiro; Lu, Gia-Hue Natalie; Roedl, Kevin; Schmidt, Claudia; Günther, Stefan; Looso, Mario; Huber, Johannes; Xu, Yong; Wiech, Thorsten; Sperhake, Jan-Peter; Wichmann, Dominic; Gröne, Hermann-Josef; Worzfeld, Thomas.
in: SCI TRANSL MED, Jahrgang 16, Nr. 767, 02.10.2024, S. eadk5005.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
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 -