Increased Elmo1 Expression worsens the AKI-CKD transition via ROS
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304219 | GEO | 2025/12/09
REPOSITORIES: GEO
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Project description:Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and presents significant challenges during kidney transplantation. Due to the detrimental effects of IRI on kidney function and the lack of effective intervention strategies, we conduct a multi-omics study on surgically induced mouse IRI, revealing a modulatory role for the metabolite S-adenosylmethionine (SAM) in AKI development. Our metabolic analysis of clinical samples establishes a link between various AKI conditions and marked elevations in serum SAM, underlying its potential as a biomarker for diagnosis. Furthermore, we find that short-term dietary methionine deprivation, which reduces circulating methionine and kidney SAM levels, effectively enhances renal resilience against IRI. In vivo isotopic tracing demonstrates that this diet preconditions kidney metabolic programs, enhancing glucose and fatty acid oxidation in preparation for IRI. Particularly, the activation of pyruvate dehydrogenase, which produces acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle, highlights an energy-efficient strategy of glucose metabolism that is essential for the protective effects of dietary methionine deprivation.
2025-12-06 | PXD058530 | Pride
Project description:Elmo1 is one member of the Elmo protein family. In our study we addressed the question if the functions of Elmo1, Elmo2 and Elmo3 are consistent or if they differ. With the CRISPR/Cas9 system we generated single knockout mutants of elmo1, elmo2 and elmo3 in the zebrafish. To assess the impact of the loss of one of the proteins on the transcriptome of a developing organism, we did RNA sequencing and transcriptome analysis with elmo1+/+ and elmo1-/-, elmo2+/+ and elmo2-/- and elmo3+/+ and elmo3-/- zebrafish larvae at 120 hours post fertilization. Here we provide the sequencing data of elmo1+/+ and elmo1-/-.
2022-07-25 | GSE197824 | 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:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1, including cathepsin G and myeloperoxidase. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed membrane proteins and v-ATPases required for bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
2021-06-05 | GSE164826 | GEO
Project description:Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and presents significant challenges during kidney transplantation. Due to the detrimental effects of IRI on kidney function and the lack of effective intervention strategies, we conduct a multi-omics study on surgically induced mouse IRI, revealing a modulatory role for the metabolite S-adenosylmethionine (SAM) in AKI development. Our metabolic analysis of clinical samples establishes a link between various AKI conditions and marked elevations in serum SAM, underlying its potential as a biomarker for diagnosis. Furthermore, we find that short-term dietary methionine deprivation, which reduces circulating methionine and kidney SAM levels, effectively enhances renal resilience against IRI. In vivo isotopic tracing demonstrates that this diet preconditions kidney metabolic programs, enhancing glucose and fatty acid oxidation in preparation for IRI. Particularly, the activation of pyruvate dehydrogenase, which produces acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle, highlights an energy-efficient strategy of glucose metabolism that is essential for the protective effects of dietary methionine deprivation.
2025-12-06 | GSE283374 | GEO
Project description:Recently, acute kidney injury (AKI) is thought to develop a predisposition toward chronic kidney disease. But the detailed mechanism of the disease progression after AKI is unknown. We made two ischemia-reperfusion injury (IRI) mice models, repaired kidney model and atrophic kidney model, and studied the mechanism that kidney after IRI became atrophy. We found that the atrophy kidney model had two peaks of apoptosis 3 and 14 days after IRI, whereas the repaired kidney model had only one apoptosis peak 3 days after IRI. We showed that the second apoptosis is responsible for the kidney atrophy. Moreover, apoptotic ligands, TNFα and FasL were upregulated at the same time of two apoptosis peaks on the atrophic kidney, and blockade of them before IRI prevented kidney from falling into atrophy. Surprisingly, inhibition of the second apoptosis by anti-TNFα antibody protected from renal atrophy. We propose that apoptosis might play a major role in AKI progression and blockade of TNFα after IRI will be a new therapeutic approach for AKI.
2012-08-10 | GSE39766 | GEO
Project description:Acute kidney injury (AKI) is a lethal syndrome with many antecedents. Transcriptomic and phenotypic investigations have demonstrated distinct patterns of renal injury which depend in part on the etiology of kidney injury. AKI following acute cardiac dysfunction is termed acute cardiorenal syndrome (CRS1). Cardiac arrest and cardiopulmonary resuscitation (CACPR) in the mouse models CRS1, and important translational insights have been generated in this model. Here, we report the results of comparison between mRNA transcriptomics performed on CACPR-exposed mouse kidneys and those obtained from IRI-exposed mouse kidney. The IRI-exposed mouse kidney data comes from the Humphreys lab (PMID: 32571916)
2025-02-14 | GSE271437 | 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:Rheumatoid arthritis is an inflammatory disease of the synovial joints that affects ~1% of the human population, with severe distress due to progressive joint inflammation and deformation. When addressing the links between specific components of the apoptotic cell clearance machinery and human disease, we noted a correlation between single nucleotide polymorphisms (SNPs) in ELMO1, DOCK2, and RAC1 genes and rheumatoid arthritis. ELMO1 is a cytoplasmic adapter protein that associates with DOCK2 and RAC1 to promote cytoskeletal reorganization needed for apoptotic cell uptake by phagocytes. We initially hypothesized that, since ELMO1 is linked to apoptotic cell clearance, loss of ELMO1 would lead to increased inflammation in arthritis. Contrary to the accumulation of apoptotic cells and greater disease severity that we predicted, we observed significantly reduced joint inflammation in two models of arthritis in mice lacking ELMO1. Using genetic and cell biological approaches in vivo and ex vivo, we determined that ELMO1 deficiency significantly reduces neutrophil recruitment to inflamed joints, but does not result in general inhibition of inflammatory responses. Through proteomic analyses, we find that ELMO1 protein associates with cellular receptors that contribute to neutrophil function in arthritis, and regulates C5a and LTB4 receptor-mediated activation and early neutrophil recruitment to the joints. Neutrophil-specific transcriptomics show that ELMO1 modulates neutrophil-specific gene expression that includes genes with known linkages to human arthritis. Finally, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to LTB4. These data identify key ‘non-canonical’ roles for engulfment machinery components in arthritis, and ELMO1 as an important regulator of specific neutrophil receptors and signaling linked to arthritis.
2019-03-19 | GSE122412 | GEO
Project description:Background Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) provide significant protection against renal ischemia-reperfusion injury (IRI). Hypoxia is considered an important method for enhancing the tissue repair capabilities of MSCs. However, the specific effects of hypoxia on MSCs and MSC-EVs, as well as their therapeutic potential for renal IRI, remain unclear. In this study, we investigated the alterations in MSCs and the production of MSC-EVs following hypoxia pre-treatment, and further explored the key intrinsic mechanisms by which hypoxic MSC-EVs treat renal IRI. Methods Human umbilical cord MSCs were cultured under normoxic and hypoxic conditions. Proliferation and related pathways were measured, and RNA sequencing was used to detect changes in the transcription profile. MSC-EVs from both normoxic and hypoxic conditions were isolated and characterized. In vivo, the localization and therapeutic effects of MSC-EVs were assessed in a rat renal IRI model. Histological examinations were employed to assess the structure, proliferation, and apoptosis of IRI kidney tissue respectively. Renal function was measured by analyzing serum creatinine and blood urea nitrogen levels. In vitro, the therapeutic potential of MSC-EVs were measured in renal tubular epithelial cells injured by antimycin A. Protein sequencing analysis of hypoxic MSC-EVs was conducted, and the depletion of Glutathione S-Transferase Omega 1 (GSTO1) in hypoxic MSC-EVs was performed to verify its key role in alleviating renal injury. Results Hypoxia alters MSCs transcription, promotes their proliferation, and increases the production of EVs. Hypoxia-pretreated MSC-EVs exhibited a superior ability to mitigate renal IRI, enhancing proliferation and reducing apoptosis of renal tubular epithelial cells both in vivo and in vitro. Protein profiling of the EVs revealed an accumulation of numerous anti-oxidative stress proteins, with GSTO1 being particularly prominent. GSTO1 knock down was significantly reduced the antioxidant and therapeutic effects in renal IRI of hypoxic MSC-EVs. Conclusions Hypoxia significantly promotes MSC-EVs generation and enhances the therapeutic effect of EVs on renal IRI. The effect of antioxidant stress induced by GSTO1 is one of the most important underlying mechanisms. Our findings underscore that hypoxia-pretreated MSC-EVs represent a novel and promising therapeutic intervention for renal IRI.
2025-05-07 | PXD057088 | Pride