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@ARTICLE{Zhou:293859,
      author       = {L. Zhou and M. T. Pereiro and Y. Li and M. Derigs and C.
                      Kuenne and T. Hielscher$^*$ and W. Huang and B. Kränzlin
                      and G. Tian and K. Kobayashi and G. N. Lu and K. Roedl and
                      C. Schmidt$^*$ and S. Günther and M. Looso and J. Huber and
                      Y. Xu and T. Wiech and J.-P. Sperhake and D. Wichmann and
                      H.-J. Gröne and T. Worzfeld},
      title        = {{G}lucocorticoids induce a maladaptive epithelial stress
                      response to aggravate acute kidney injury.},
      journal      = {Science translational medicine},
      volume       = {16},
      number       = {767},
      issn         = {1946-6234},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DKFZ-2024-01989},
      pages        = {eadk5005},
      year         = {2024},
      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.},
      keywords     = {Animals / Acute Kidney Injury: metabolism / Acute Kidney
                      Injury: pathology / Humans / Glucocorticoids: adverse
                      effects / Glucocorticoids: pharmacology / COVID-19:
                      complications / COVID-19: metabolism / Mice / Epithelial
                      Cells: metabolism / Epithelial Cells: drug effects /
                      Epithelial Cells: pathology / Receptors, Glucocorticoid:
                      metabolism / Disease Models, Animal / Male / Kidney Tubules:
                      pathology / Kidney Tubules: metabolism / Kidney Tubules:
                      drug effects / Myoglobin: metabolism / Dexamethasone:
                      pharmacology / Dexamethasone: adverse effects / Stress,
                      Physiological: drug effects / SARS-CoV-2 / Mice, Inbred
                      C57BL / Female / Glucocorticoids (NLM Chemicals) /
                      Receptors, Glucocorticoid (NLM Chemicals) / Myoglobin (NLM
                      Chemicals) / Dexamethasone (NLM Chemicals)},
      cin          = {C060 / W210},
      ddc          = {500},
      cid          = {I:(DE-He78)C060-20160331 / I:(DE-He78)W210-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39356748},
      doi          = {10.1126/scitranslmed.adk5005},
      url          = {https://inrepo02.dkfz.de/record/293859},
}