Effects of circAASS overexpression in human HK2 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE286356 | GEO | 2026/03/01
REPOSITORIES: GEO
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Project description:Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with an increased morbidity and mortality. Currently, no effective treatment options are available. Here, we show that glutamine significantly attenuates leukocyte recruitment and inflammatory signaling in human and murine tubular epithelial cells (TECs). In a murine AKI model induced by ischemia-reperfusion-injury (IRI) we show that glutamine causes transcriptomic and proteomic reprogramming in renal TECs and neutrophils, resulting in decreased epithelial apoptosis, 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. Increased Tgm2 expression and reduced Ask1 activation result in decreased JNK activation leading to a diminished mitochondrial intrinsic apoptosis in kidneys upon IRI-induced AKI and under hypoxia or following TNFα-treatment of TECs. Consequently, glutamine administration attenuated kidney injury in vivo during AKI progression as well as TEC viability in vitro under inflammatory and hypoxic conditions.
2023-03-11 | PXD029723 | Pride
Project description:Ischemia/reperfusion-induced acute kidney injury (AKI) occurs in several clinical conditions accompanied by inflammation, but the underlying mechanisms remain elusive. The Wnt inhibitor Tiki2 is highly expressed in the kidney with unknown function. Here, we demonstrated that Tiki2 is highly expressed in proximal tubular epithelial cells (PTECs) and is dynamically regulated in AKI. Tubular epithelial cell-specific ablation of Tiki2 aggravated immune cell infiltration and tubular injury in IR-induced AKI. Mechanistically, Tiki2 ablation increased the activity of Wnt5a/Ror signaling, which is activated in PTECs in IR-induced AKI, leading to increased active JNK/ERK signaling and the secretion of chemokines and cytokines to promote the infiltration of immune cells. Furthermore, the increased severity of injury and inflammation caused by Tiki2 ablation could be relieved by knocking down Ror2 in PTECs. Our study reveals the critical roles of Wnt5a/Ror signaling and its negative regulator Tiki2 in IR-induced AKI, which are potential therapeutic targets for treating AKI
2025-04-08 | GSE293486 | GEO
Project description:Inflammation plays a crucial role in the development of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) following renal ischemia-reperfusion (IR). It has been demonstrated that metabolites from the gut microbiota can trigger inflammatory responses and modulate renal damage induced by IR. However, the exact driving factors and underlying mechanisms of this process remain unclear. Trimethylamine N-oxide (TMAO), a choline metabolite derived from the gut, has been observed to increase in AKI and CKD patients. Our study reveals that glycyrrhizic acid (GA) exacerbates IR-induced AKI and subsequent CKD through TMAO. To delve into the underlying mechanisms, we employed single-cell sequencing to construct a molecular map of kidney cells.
2024-09-09 | GSE244890 | 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 | 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:Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear.results of this study in a renal ischemia-reperfusion injury model allow phenotype and function to be assigned to CD11b+/Ly6C+ monocyte/macrophage populations in the pathophysiology of disease after AKI. we used a renal bilateral ischemia-reperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b+Â cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies Macrophage populations were sorted by Flow Cytometry into low and intermediate populations by Itgam(Cd11b) and Ly6c markers. The cells obtained in 5 weeks sham, 5 weeks IR, 9 day sham, and 9 day IR with 6 samples per group (3 int and 3 low). Cells were sorted in 350ul of RLT lysing buffer and kept at -80c until RNA extraction.Sample amplification, fragmentation, hybridization,washing and scanning were performed according to validated Affymetrix protocol in a CLIA certified lab.
2015-12-09 | E-GEOD-75808 | biostudies-arrayexpress
Project description:Acute kidney injury (AKI) is rapidly increasing and becomes a major of public health problem nowadays. However, its underlying mechanism has not been elucidated. Studies have shown that cluster of differentiation-44 (CD44) play a role in the pathological process of AKI. Nevertheless, the molecule mechanism has not been totally clarified. Herein, we found that CD44 is increased in renal tubules in ischemia-reperfusion injury (IRI)-induced AKI mice. Knockout of CD44 improved mitochondrial biogenesis and mitochondrial fatty acid oxidation (FAO), further protecting against renal tubular cell apoptosis and kidney injury. Conversely, ectopic expression of CD44 impaired mitochondrial function and FAO, which exacerbated the pathological process of AKI. Transcriptome sequencing revealed NF-κB p65 is highly responsible for this process. In vitro, we found that CD44 induced activation of NF-κB p65 via mitogen-activated protein kinase (MAPK) ERK1/2 and MAPK p38, further transcriptionally silencing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoters. As a result, downregulation of PGC-1α contributed to impairment of mitochondrial dysfunction and FAO, resulting in the deterioration of AKI. Our study found that inhibiting CD44 is a new potential therapeutic strategy for AKI through promoting mitochondrial biogenesis and FAO. The underlying mechanism is associated with MAPK/p65/ PGC-1α pathway.
2025-02-26 | GSE252060 | GEO
Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.
2023-10-10 | GSE159701 | GEO
Project description:Perturbations in proximal tubule mitochondrial function and lipid metabolism potentiate kidney dysfunction in acute kidney injury (AKI). We identified the bioactive lipid ceramides as drivers of proximal tubule pathology in AKI. Ceramide synthesis was upregulated in humans and mice with AKI. We utilized a proteome-wide thermal shift assay to observe that ceramides interact with proximal tubule proteins involved in lipid and mitochondrial metabolism. Mechanistic studies revealed that ceramides altered assembly of the inner mitochondrial membrane MICOS complex and respiratory supercomplexes in proximal tubule cells leading to acute impacts on mitochondrial respiration, cristae architecture, and mitochondrial morphology. Effects of ceramides on complex assembly and mitochondrial function were dependent on the presence of the 4-5 trans double bond incorporated by dihydroceramide desaturase 1 (DES1). Blunting ceramide synthesis, via genetic or pharmacologic inhibition of DES1, prevented kidney injury in mice following renal ischemia reperfusion injury. Ceramides may be a novel therapeutic target to combat mitochondrial disruption during AKI.
2025-12-17 | GSE284451 | GEO
Project description:Preconditioning strategies like caloric restriction (CR) and hypoxic preconditioning (HP) show remarkable protective effects in animal models of acute kidney injury (AKI). Since the underlying molecular effects are still not fully understood we performed an experiment directly comparing CR and HP in a murine model of ischemia-reperfusion injury (IRI) of the kidney. 8 to 12-week-old, male C57BL6/J mice were either put to 4 weeks of caloric restriction (70% of normal food intake) or placed in a hypoxic chamber (8%O2) for 3 consecutive days prior to IRI. Whole kidneys were used for transcriptional analysis (RNAseq) before and after ischemia-reperfusion injury to look for common effects of both modes of preconditioning.
2019-12-31 | E-MTAB-7982 | biostudies-arrayexpress