机构：[1]Institute of Pharmacology, University of Marburg, Karl-von-Frisch-StraBe 2, Marburg 35043, Germany.[2]Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Taiping Street 25, Luzhou 646000, China.[3]Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Taiping Street 25, Luzhou 646000, China.[4]Department of Urology, University Hospital, University of Marburg, BaldingerstraBe, Marburg 35043, Germany.[5]Bioinformatics, Max Planck Institute for Heart and Lung Research, LudwigstraBe 43, Bad Nauheim 61231, Germany.[6]Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.[7]Core Facility Preclinical Models, Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-StraBe 13-17, Mannheim 68167, Germany.[8]Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Taiping Street 25, Luzhou 646000, China.[9]Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany.[10]Light Microscopy Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.[11]Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, LudwigstraBe 43, Bad Nauheim 61231, Germany.[12]Institute of Pathology, Nephropathology Section, University Medical Center Hamburg-Eppendorf, MartinistraBe 52, Hamburg 20246, Germany.[13]Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Butenfeld 34, Hamburg 22529, Germany.[14]Medical Faculty, University of Heidelberg, Heidelberg 69120, Germany.
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.
基金：
This work was
supported by grants from the Authorities for Social Welfare (Hamburger Behörde für Arbeit,
Soziales, Familie und Integration), Hamburg, Germany, and as part of the National Autopsy
Network (NATON) by the Network University Medicine (BMBF grant number 01KX2121) to
J.-P.
S. and T. Wiech and by funds from the University of Marburg to T. Worzfeld.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类|1 区医学
小类|1 区细胞生物学1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区细胞生物学1 区医学：研究与实验
第一作者：
第一作者机构：[1]Institute of Pharmacology, University of Marburg, Karl-von-Frisch-StraBe 2, Marburg 35043, Germany.[2]Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Taiping Street 25, Luzhou 646000, China.[3]Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Taiping Street 25, Luzhou 646000, China.
通讯作者：
推荐引用方式(GB/T 7714)：
Zhou Luping,Pereiro Marc Torres,Li Yanqun,et al.Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury[J].Science Translational Medicine.2024,16(767):eadk5005.doi:10.1126/scitranslmed.adk5005.
APA：
Zhou Luping,Pereiro Marc Torres,Li Yanqun,Derigs Marcus,Kuenne Carsten...&Worzfeld Thomas.(2024).Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury.Science Translational Medicine,16,(767)
MLA：
Zhou Luping,et al."Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury".Science Translational Medicine 16..767(2024):eadk5005
医学