Gut-Derived Metabolite Trimethylamine N-Oxide Promotes Inflammation and Fibrosis Following Ischemia/Reperfusion through CCR2-Mediated Macrophage Infiltration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE244890 | GEO | 2024/09/09
REPOSITORIES: GEO
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Project description:Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counter-acted the suppressive effect of TMAO on megalin expression. Our results may further help us un-ravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.
2022-08-10 | GSE210692 | GEO
Project description:<p>Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.</p><p><br></p><p>Linked study:</p><p><strong>UPLC-MS assay</strong> of mice kidney tissue sacrificed at<strong> day 10 </strong>after UIR is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3056' rel='noopener noreferrer' target='_blank'>MTBLS3056</a></p>
2021-07-22 | MTBLS3003 | MetaboLights
Project description:<p>Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.</p><p><br></p><p>Linked study:</p><p><strong>UPLC-MS assay</strong> of mice kidney tissues sacrificed at <strong>day 21 </strong>after UIR is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS3003' rel='noopener noreferrer' target='_blank'>MTBLS3003</a></p>
2021-07-22 | MTBLS3056 | MetaboLights
Project description:Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-β suppressed TNF-α- and IL-1β-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.
2024-09-03 | GSE254359 | GEO
Project description:We found that PTC undergo polyploidization immediately after glycerol-induced rhabdomyolysis (nephrotoxic-AKI). Polyploidization of PTC is controlled by YAP1. Block of YAP1 related polyploidization of TC employing a specific inhibitor of YAP1 transcriptional activity (CA3) after the acute phase of damage prevented CKD progression after AKI. To identify novel pathways and potential targets involved in AKI response and subsequent CKD development, we generated single-cell RNA sequencing (scRNAseq) datasets from nephrotoxic-AKI female mice treated with vehicle or CA3 starting from 4 days after AKI. Mice were sacrificed two weeks after AKI, when blood urea nitrogen levels, that reflect kidney functionality, were found to start diverging between treated and control mice, but before CKD development.
2024-11-01 | GSE232576 | GEO
Project description:Mammalian kidney has very limited ability to repair or regenerate after acute kidney injury (AKI). The maladaptive repair of AKI promotes the progression to chronic kidney disease (CKD). Therefore, it is extremely urgent to explore new strategies to promote the repair/regeneration of injured renal tubules after AKI. It has been shown that hypoxia induces heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxia condition and found that MK-8617 significantly ameliorates ischemia reperfusion injury (IRI) induced acute kidney injury. We then showed that MK-8617 dramatically facilitates renal regeneration via promoting the proliferation of injured renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis- related genes were significantly upregulated with MK-8617 pretreatment. Furthermore, we showed that MK-8617 may alleviate proximal tubule injury via stabilizing HIF-1α protein specifically in renal proximal tubular cells. We also demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells, and the regeneration of renal proximal tubules. In summary, we discovered that inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI via promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.
2024-10-10 | GSE247560 | GEO
Project description:Sepsis induced acute kidney injury (AKI) is associated with a rapid decline of kidney function, leading to unacceptably high morbidity and mortality rate as well as progression to chronic kidney disease (CKD). We have recently developed a septic AKI mouse model. By quantitatively assessing the kidney proteome and phosphoproteome changes upon bacterial infection, we accurately quantified over 2,200 kidney proteins with high confidence, which provided us the first global overview of the extensively remodeled kidney proteome and revealed widespread metabolic and oxidation-reduction processes undergone in septic kidney. This data will give us unprecedented insight into how renal cells response to microbe invasion, and will likely serve as a reference dataset of systems biology.
2020-09-25 | PXD017045 | Pride
Project description:Kidney damage involves the progressive and inexorable destruction of tubular and glomerular system. However, it is known that the patients survive AKI often recover renal structure and function. Correspondingly, previous studies demonstrated tubular regeneration in mice after massive kidney injury and linked mouse Sox9+ renal progenitor cells to this process. Here we show that renal progenitor cells can be cloned from renal needle biopsy sample of CKD patients. Progenitor cells can readily assembly into “kidney organoids” expressing proximal/distal tubular cell markers in 3D culture.
2022-04-22 | GSE119426 | GEO
Project description:Men are more prone to acute kidney injury (AKI) and chronic kidney disease (CKD), progressingto end-stage renal disease (ESRD) than women. Severity and capacity to regenerate after AKI are important determinants of CKD progression, and of patient morbidity and mortality in the hospital setting. To determine sex diferences during injury and recovery we have generated a female and male renal ischemia/reperfusion injury (IRI) pig model, which represents a major cause of AKI. This study was conducted using farm pigs, hybrids between Large White and Landrace. Five females and five males of four months old, free of specifc pathogens, between 30 and 40 kg of weight were included in this study. This age range was chosen due to the sexual maturity of the animal, allowing hormone efects. Using microarray assays, global transcriptomic analyses of kidney biopsies from this IRI pig model was conducted and revealed a sexual dimorphism in the temporal regulation of genes and pathways relevant for kidney injury and repair. Overall, this study constitutes an extensive characterization of the time and sex diferences occurring during renal IRI and recovery at gene expression level.
2024-03-02 | GSE259281 | GEO
Project description:Acute kidney injury (AKI) is a critical condition marked by a sudden decline in kidney function, often triggered by ischemia-reperfusion (IR) injury. Its pathophysiology involves inflammation, oxidative stress, and endoplasmic reticulum (ER) stress. Recently, protein tyrosine phosphatase 1B (PTP1B) has been highlighted as a therapeutic target for ischemic disease due to its potential implication in activating ER stress. In this study, we observed significant overexpression of PTP1B in human kidney tissues during AKI. Additionally, in mouse models of AKI, we confirmed that this overexpression is associated with the upregulation of ER stress and inflammatory pathways mediated by Src. To explore the effect of PTP1B inhibition in AKI, we employed PTP1B-targeting siRNA (PTPi) delivered via extracellular vesicles derived from commercial milk (mEVs). PTPi@mEVs effectively reduced PTP1B expression in proximal tubular cells, decreasing ER stress and Src kinase activation. In an IR-AKI mouse, PTPi@mEVs alleviated renal dysfunction, reduced cell death, and restored gene expression related to inflammation, ROS, and ER stress. Histological analysis confirmed that PTP1B knockdown mitigated tight junction disruption in renal tissue. These findings underscore the therapeutic potential of targeting PTP1B to mitigate AKI symptoms, highlighting the efficacy of mEVs-mediated PTPi delivery in reducing acute inflammatory responses and renal dysfunction.
2024-07-08 | GSE271279 | GEO