Journal Article

DKFZ-2024-01989

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury.

Zhou, L. ; Pereiro, M. T. ; Li, Y. ; Derigs, M. ; Kuenne, C. ; Hielscher, T.DKFZ* ; Huang, W. ; Kränzlin, B. ; Tian, G. ; Kobayashi, K. ; Lu, G. N. ; Roedl, K. ; Schmidt, C.DKFZ* ; Günther, S. ; Looso, M. ; Huber, J. ; Xu, Y. ; Wiech, T. ; Sperhake, J.-P. ; Wichmann, D. ; Gröne, H.-J. ; Worzfeld, T.

2024
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.adk5005

Abstract: 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.

Keyword(s): Animals (MeSH) ; Acute Kidney Injury: metabolism (MeSH) ; Acute Kidney Injury: pathology (MeSH) ; Humans (MeSH) ; Glucocorticoids: adverse effects (MeSH) ; Glucocorticoids: pharmacology (MeSH) ; COVID-19: complications (MeSH) ; COVID-19: metabolism (MeSH) ; Mice (MeSH) ; Epithelial Cells: metabolism (MeSH) ; Epithelial Cells: drug effects (MeSH) ; Epithelial Cells: pathology (MeSH) ; Receptors, Glucocorticoid: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Male (MeSH) ; Kidney Tubules: pathology (MeSH) ; Kidney Tubules: metabolism (MeSH) ; Kidney Tubules: drug effects (MeSH) ; Myoglobin: metabolism (MeSH) ; Dexamethasone: pharmacology (MeSH) ; Dexamethasone: adverse effects (MeSH) ; Stress, Physiological: drug effects (MeSH) ; SARS-CoV-2 (MeSH) ; Mice, Inbred C57BL (MeSH) ; Female (MeSH) ; Glucocorticoids ; Receptors, Glucocorticoid ; Myoglobin ; Dexamethasone

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Contributing Institute(s):

1. C060 Biostatistik (C060)
2. Lichtmikroskopie (W210)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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