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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.