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Project description:Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality. 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 analyses of mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocortiocoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of the widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse kidney tubuloids. Mechanistically, studies in mouse tubuloids demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair and to amplify injury-induced DNA double-strand break formation, as well as to dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocortiocoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for acute kidney injury.
2024-09-14 | GSE276041 | GEO
Project description:Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality. 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 analyses of mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocortiocoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of the widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse kidney tubuloids. Mechanistically, studies in mouse tubuloids demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair and to amplify injury-induced DNA double-strand break formation, as well as to dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocortiocoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for acute kidney injury.
2024-09-14 | GSE276040 | GEO
Project description:Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury
| PRJNA1154554 | ENA
Project description:Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury [RNA]
| PRJNA1154560 | ENA
Project description:Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury [ATAC]
| PRJNA1154561 | ENA
Project description:Purpose of reviewDespite improvements in acute kidney injury (AKI) detection, therapeutic options to halt the progression of AKI to chronic kidney disease (CKD) remain limited. In this review, we focus on recent discoveries related to the pathophysiology of the AKI to CKD continuum, particularly involving the renal tubular epithelial cells, and also discuss related ongoing clinical trials. While our focus is on injured renal tubular epithelial cells as initiators of the cascade of events resulting in paracrine effects on other cells of the kidney, the summation of maladaptive responses from various kidney cell types ultimately leads to fibrosis and dysfunction characteristic of CKD.Recent findingsRecent findings that we will focus on include, but are not limited to, characterizations of: the association between cell cycle arrest and cellular senescence in renal tubular epithelial cells and its contribution to renal fibrosis, chronic inflammation with persistent cytokine production and lymphocyte infiltration among unrepaired renal tubules, mitochondrial dysfunction and a unique role of cytosolic mitochondria DNA in fibrogenesis, prolyl hydroxylase domain proteins as potential therapeutic targets, and novel mechanisms involving the Hippo/yes-associated protein/transcriptional coactivator with PDZ-binding pathway.SummaryPotential therapeutic options to address CKD progression will be informed by a better understanding of fibrogenic pathways. Recent advances suggest additional drug targets in the various pathways leading to fibrosis.
| S-EPMC7363449 | biostudies-literature
Project description:Circulating plasma extracellular vesicles (EVs) mostly originate from platelets and may promote organ dysfunction in sepsis. However, the role of platelet-derived EVs in sepsis-induced acute kidney injury (AKI) remains poorly understood. The present study extracted EVs from the supernatant of human platelets treated with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). Then, we subjected PBS-EVs or LPS-EVs to cecal ligation and puncture (CLP) mice in vivo or LPS-stimulated renal tubular epithelial cells (RTECs) in vitro. Our results indicated that LPS-EVs aggravate septic AKI via promoting apoptosis, inflammation and oxidative stress. Further, ADP-ribosylation factor 6 (ARF6) was identified as a differential protein between PBS-EVs and LPS-EVs by quantitative proteomics analysis. Mechanistically, ARF6 activated ERK/Smad3/p53 signaling to exacerbate sepsis-induced AKI. LPS upregulated ARF6 in RTECs was dependent on TLR4/MyD88 pathway. Both genetically and pharmacologically inhibition of ARF6 attenuated septic AKI. Moreover, platelets were activated by TLR4 and its downstream mediator IKK controlled platelet secretion during sepsis. Inhibition of platelet secretion alleviated septic AKI. Collectively, our study demonstrated that platelet-derived EVs may be a therapeutic target in septic AKI.
| S-EPMC10620832 | biostudies-literature
Project description:BackgroundAcute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood.MethodsWe performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1-2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI.ResultsHigh-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar.ConclusionsThe study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.
| S-EPMC9462075 | biostudies-literature
Project description:Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia/reperfusion injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, decreased neutrophil recruitment, and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Furthermore, the direct modulation of the Tgm2-HSP70 signalosome and reduced Ask1 activation resulted in decreased JNK activation, leading to diminished mitochondrial intrinsic apoptosis in TECs. Glutamine administration attenuated kidney damage in vivo during AKI and TEC viability in vitro under inflammatory or hypoxic conditions.
| S-EPMC9675453 | biostudies-literature
Project description:Acute kidney injury (AKI) is a common and significant medical problem. Despite the kidney's remarkable regenerative capacity, the mortality rate for the AKI patients is high. Thus, there remains a need to better understand the cellular mechanisms of nephron repair in order to develop new strategies that would enhance the intrinsic ability of kidney tissue to regenerate. Here, using a novel, laser ablation-based, zebrafish model of AKI, we show that collective migration of kidney epithelial cells is a primary early response to acute injury. We also show that cell proliferation is a late response of regenerating kidney epithelia that follows cell migration during kidney repair. We propose a computational model that predicts this temporal relationship and suggests that cell stretch is a mechanical link between migration and proliferation, and present experimental evidence in support of this hypothesis. Overall, this study advances our understanding of kidney repair mechanisms by highlighting a primary role for collective cell migration, laying a foundation for new approaches to treatment of AKI.
| S-EPMC4092191 | biostudies-literature