Glutamine attenuates renal ischemia-reperfusion injury and prevents acute kidney damage
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188628 | GEO | 2021/11/13
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:Glutamine attenuates renal ischemia-reperfusion injury and prevents acute kidney damage
| PRJNA779717 | ENA
Project description:characterization of fibrinogen expression in the kidney, excretion in the urine following kidney damage and evaluating the therapeutic potential of fibrinogen in acute kidney injury. Total RNA was isolated of renal cortex and medulla from rats subjected to 20 min of bilateral ischemia followed by 6, 24 120, hr of reperfusion compared to sham rats.
2011-09-30 | E-GEOD-27274 | biostudies-arrayexpress
Project description:characterization of fibrinogen expression in the kidney, excretion in the urine following kidney damage and evaluating the therapeutic potential of fibrinogen in acute kidney injury.
2011-10-01 | GSE27274 | GEO
Project description:Our study investigates how RIPC modulates the transcriptomic profile of neutrophils and renal tubular epithelial cells in the kidney during acute kidney injury.
2022-06-16 | GSE206091 | GEO
Project description:Background & aimsHepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo pathway, is essential for determining cell fate and maintaining homeostasis in the liver. We aimed to elucidate its role in IRI.MethodsThe role of YAP/Hippo signaling was systematically studied in biopsy specimens from 60 patients after orthotopic liver transplantation (OLT), and in a mouse model of liver warm IRI. Human biopsy specimens were collected after 2-10 h of cold storage and 3 h post-reperfusion, before being screened by western blot. In the mouse model, the role of YAP was probed by activating or inhibiting YAP prior to ischemia-reperfusion.ResultsIn human biopsies, high post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at postoperative day 1-7. In mice, the ischemia insult (90 min) triggered intrinsic hepatic YAP expression, which peaked at 1-6 h of reperfusion. Activation of YAP protected the liver against IR-stress, by promoting regenerative and anti-oxidative gene induction, while diminishing oxidative stress, necrosis/apoptosis and the innate inflammatory response. Inhibition of YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In mouse hepatocyte cultures, activating YAP prevented hypoxia-reoxygenation induced stress. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cell (HSC) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSC activation, and enhanced liver fibrosis at 7 days post-IRI. Notably, YAP activation failed to protect Nrf2-deficient livers against IR-mediated damage, leading to extensive fibrosis.ConclusionOur novel findings document the crucial role of YAP in IR-mediated hepatocellular damage and liver fibrogenesis, providing evidence of a potential therapeutic target for the management of sterile liver inflammation in transplant recipients.Lay summaryIn the clinical arm, graft YAP expression negatively correlated with liver function and tissue damage after human liver transplantation. YAP activation attenuated hepatocellular oxidative stress and diminished the innate immune response in mouse livers following ischemia-reperfusion injury. In the mouse model, YAP inhibited hepatic stellate cell activation, and abolished injury-mediated fibrogenesis up to 7 days after the ischemic insult.
| S-EPMC6773499 | biostudies-literature
Project description:Acute kidney injury (AKI) is associated with an increased risk of chronic kidney disease (CKD). To extend our understanding of renal repair, and its limits, we performed a detailed molecular characterization of a murine ischemia reperfusion injury (IRI) model for 12 months post injury. RNA-seq analysis highlights a cascade of temporal specific gene expression patterns related to tubular injury/repair, fibrosis, innate and adaptive immunity.
2017-09-12 | GSE98622 | GEO
Project description:Mitochondrial dynamics is a possible modulator of myocardial ischemia/reperfusion injuries (IRI). We previously reported that mice partially deficient in the fusion protein OPA1 exhibited higher IRI. Therefore, we investigated whether deficiency in the fission protein DRP1 encoded by Dnm1l gene would affect IRI in Dnm1l+/- mouse. After baseline characterization of the Dnm1l+/- mice heart, using echocardiography, electron microscopy, and oxygraphy, 3-month-old Dnm1l+/- and wild type (WT) mice were exposed to myocardial ischemia/reperfusion (I/R). The ischemic area-at-risk (AAR) and area of necrosis (AN) were delimited, and the infarct size was expressed by AN/AAR. Proteins involved in mitochondrial dynamics and autophagy were analyzed before and after I/R. Mitochondrial permeability transition pore (mPTP) opening sensitivity was assessed after I/R. Heart weight and left ventricular function were not significantly different in 3-, 6- and 12-month-old Dnm1l+/- mice than in WT. The cardiac DRP1 protein expression levels were 60% lower, whereas mitochondrial area and lipid degradation were significantly higher in Dnm1l+/- mice than in WT, though mitochondrial respiratory parameters and mPTP opening did not significantly differ. Following I/R, the infarct size was significantly smaller in Dnm1l+/- mice than in WT (34.6±3.1% vs. 44.5±3.3%, respectively; p<0.05) and the autophagic markers, LC3 II and P62 were significantly increased compared to baseline condition in Dnm1l+/- mice only. Altogether, data indicates that increasing fusion by means of Dnm1l deficiency was associated with protection against IRI, without alteration in cardiac or mitochondrial functions at basal conditions. This protection mechanism due to DRP1 haploinsufficiency increases the expression of autophagic markers.
| S-EPMC7993837 | biostudies-literature
Project description:DNA-binding protein-A (DbpA; gene: Ybx3) belongs to the cold shock protein family with known functions in cell cycling, transcription, translation and tight junction communication. In chronic nephritis DbpA is upregulated, however its activities in acute injury models, such as renal ischemia/reperfusion injury (IRI), are unclear. Mice harboring Ybx3+/+, Ybx3+/- or Ybx3-/- genotype were characterized over a period of 24 months and following experimental renal IRI. Mitochondrial function, number and integrity were analyzed by mito stress tests, MitoTracker staining and electron microscopy. Immunohistochemistry, Western blotting and flow cytometry were performed to quantify tubular cell damage and immune cell infiltration. DbpA is dispensable for kidney development and tissue homeostasis under healthy conditions. Furthermore, endogenous DbpA protein localizes within mitochondria in primary tubular epithelial cells (TECs). Genetic deletion of Ybx3 elevates the mitochondrial membrane potential, the lipid uptake and metabolism, the oxygen consumption rates (OCR) and glycolytic activities of TECs. Ybx3-/- mice demonstrate protection from IRI with less immune cell infiltration, ER stress and tubular cell damage. A putative protective mechanism is identified via upregulated antioxidant activities and reduced ferroptosis, when Ybx3 is deleted. Here, experimental evidences reveal DbpA acts as a mitochondrial protein with profound adverse effects on cell metabolism and highlights a protective effect against IRI when Ybx3 is genetically deleted.
2024-04-26 | GSE264448 | GEO
Project description:Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects.
| S-EPMC3761629 | biostudies-literature