TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner

Genes, Journal Year: 2023, Volume and Issue: 14(3), P. 591 - 591

Published: Feb. 26, 2023

Cardiac fibrosis and cardiomyocyte apoptosis are reparative processes after myocardial infarction (MI), which results in cardiac remodeling heart failure at last. Tenascin-C (TNC) consists of four distinct domains, is a large multimodular glycoprotein the extracellular matrix. It also key regulator proliferation cardiomyocytes. As significant m6A regulator, METTL3 binds sites mRNA to control its degradation, maturation, stabilization, translation. Whether regulates occurrence development through modification TNC deserves our study. Here, we have demonstrated that overexpression aggravated dysfunction 4 weeks MI. Moreover, resulted Mechanistically, led enhanced levels promoted stability. Then, mutated one site “A” “T”, binding ability was reduced. In conclusion, involved by increasing may be promising target for therapy

Language: Английский

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FTO‐mediated m⁶A modification of SOCS1 mRNA promotes the progression of diabetic kidney disease

Clinical and Translational Medicine, Journal Year: 2022, Volume and Issue: 12(6)

Published: June 1, 2022

N6-methyladenosine (m6A) is the most prominent and frequent internal messenger RNA (mRNA) modification plays diverse roles in regulating functions of modified transcripts.1 However, role m6A kidney disease remains rarely understood, especially at onset diabetic (DKD).2 Here, we delineate biological FTO-mediated DKD through imaging mass cytometry (IMC), LC/MS, RNASeq methods. The results show that loss levels by overexpressing FTO recapitulated human increasing expression suppressors cytokine signalling 1 (SOCS1) protein level to alleviate inflammation response injury. Thus, maybe a potential therapeutic target for patients. To quantify cellular spatial levels, designed an IMC panel specific histology used this analyse biopsies (Figure 1A Table S1). integrates IHC using metal isotope-tagged antibodies with laser ablation mass-spectrometry-based detection produce high-dimensional images,3 which allow simultaneously quantified its regulators. We identified 17 676 cells m6A, regulators, characteristics single-cell (Figures five dominant cell clusters proximal tubules, distal convoluted tubule, glomerulus (Glom) endothelial, macrophage, stromal populations.4 data demonstrated were significantly increased several types cells, was reduced 2). suggest important dynamics DKD. Further analysis revealed serum upregulated T2D patients S2 S3a). showed downregulated patients, whereas other regulators remained unchanged S3b S4). also negatively correlated S3c–e). Furthermore, re-analyses public datasets decreased or uremina S3f–h). further investigate pathogenesis, high-concentration glucose (HG) treatment simulate phenotypes DKD.5 HG expression, S5a–d). Moreover, after S6). overexpression knock-down augmented respectively S5e–h). often triggers glucose-response transcriptional factor ChREBP expression,6 promoter had ChREBP-binding sites, indicating may suppress via activating S5i). Together, these reveal are due downregulation molecular mechanism how dysregulated involved performed MeRIP-seq HMC overexpression, peaks enriched 3′-UTR region 3A,C) characterized RAACH motif 3B). Overall, 25 genes affected both levels. Pathway enrichment analyses 3D,E Tables S6 S7). More specifically, SOCS1, key regulator inflammation, 3F), confirmed S7a). MeRIP-qPCR SOCS1 on 3G). when overexpressed 3H). mRNA positively associated S7b). suppressed S7c). inhibition induced could result S7d). demethylation-inactive mutant (H231A D233A) no effects compared wild-type S7e 3I).Moreover, FTO-RIP-qPCR assays direct binding 3J). Our findings indicate can increase removing m6A. Inflammation vital DKD, considered regulator.8, 9 Network GSEA inflammation-related pathways including JAK-STAT pathway repressed S8a,b). inhibited inhibiting JAK2/STAT3 phosphorylation. In contrast, aggravated promoting phosphorylation S8c–e). rescue assay p-JAK2 p-STAT3 S8f). Collectively, activated expression. generated db/db mice commonly T2D/DKD model.10 Intriguingly, injecting fto-overexpressing lentivirus alleviated damage, fto might be S9a–g). LC/MS higher mice, FTO-overexpressing 4A S9h). qRT-PCR microarray various mouse models S9i–m). WB socs1 led jak2 stat3 4B,C S10). Surprisingly, as H&E, PAS, SR, indicated attenuated injuries fibrosis. our injury suppression inflammation. conclusion, protective during pathogenesis. Mechanistically, FTO/SOCS1/JAK-STAT axis promotes pathogenesis 4D). dramatically Therefore, targeting combination current approaches new avenue treatment. No conflicts interest relevant article reported. Supporting Information Figure S1 Quality evaluation tissues: (a) dot bolt synthetic fragments without modification; (b) summary example images all 10 markers from different analysed cohort; (c) t-SNE plot showing batch effect Vimentin, aSMA, Nephrin, CD68, Aquaporin II, Collagen IV, E-cadherin each type cell. Detection LC-MS/MS method: calibration curve (top panel) A (bottom detected LC-MS/MS; chromatograms (red) (blue) samples T2D, healthy volunteers LC-MS/MS. S3 Decreased patients: overall LC–MS/MS; heat map shows pattern 15 samples. Five replicates group; another cohort (d) qPCR 2; (e) correlation between (f) blood uraemia GSE37171 dataset; (g,h) glomeruli DN GSE96804 (g) GSE30122 (h) datasets. Data represented mean ± s.e.m. Statistical two-tailed unpaired student t-tests corrected multiple comparisons Holm-Sidak method. S4 Expression volunteers: PCA sequencing regressing out batch, sex age controls, serums (n = 5 group); (b c) YTHDC2 HNRNPA2B1 1. S5 High-concentration reducing expression: HK-2 glucose, normal-concentration mannitol; Western blot proteins mannitol cells; overexpression; knock-down; (i) presented JASPAR database schematic illustration sites FTO. treatment: (a–d) METTL3 (a), (c), ALKBH5 mannitol. S7 FTO: abundances transcripts MONOMAC-6 GSE76414 plotted; empty vector, plasmid. S8 Loss JAK2 STAT3: Protein–protein interaction network according STRING analysis; altered base data, NES, normalized score; treatments. S9 vivo experiments value fto: (a–c) Body weight (b), index db/m, injected control virus, ftooverexpression lentivirus; (d–g) urinary (d), creatinine (e), (f), urea nitrogen relative db/m mice; (i–m) ftoexpression models. S10 Quantification lentivirus: 4 lentivirus. Please note: publisher not responsible content functionality any supporting information supplied authors. Any queries (other than missing content) should directed corresponding author article.

Language: Английский

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Enhancer and super-enhancer landscape in polycystic kidney disease

Kidney International, Journal Year: 2022, Volume and Issue: 103(1), P. 87 - 99

Published: Oct. 22, 2022

Language: Английский

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The potential role of N6-methyladenosine modification of LncRNAs in contributing to the pathogenesis of chronic glomerulonephritis

Inflammation Research, Journal Year: 2023, Volume and Issue: 72(3), P. 623 - 638

Published: Jan. 26, 2023

Language: Английский

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Methyltransferase-like 3 mediates m6A modification of heme oxygenase 1 mRNA to induce ferroptosis of renal tubular epithelial cells in acute kidney injury

Free Radical Biology and Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Acute kidney injury (AKI) involves a series of syndromes characterized by rapid increase in creatinine levels. Ferroptosis, as an iron-dependent mode programmed cell death, reportedly participates the pathogenesis AKI. Methyltransferase-like 3 (METTL3)-mediated m6A modification has been recently associated with various diseases; however, mechanism METTL3 crosstalk molecules involved ferroptosis is not clearly understood. Here, we investigated between METTL3-mediated and was elevated patients AKI, FA-AKI mice, TBHP-stimulated TCMK-1 cells. Inhibition expression vivo vitro alleviated damage renal tubular MeRIP sequencing showed that heme oxygenase 1 (Hmox1/HO-1) target. RIP-qPCR indicated anti-insulin-like growth factor 2 mRNA binding protein 3(IGF2BP3) could be used reader to bind methylated site Hmox1 maintain its stability. knockdown reduced accumulation iron ions ferroptosis. mediates maintains stability IGF2BP3-dependent manner, which causes overload epithelial cells, leading

Language: Английский

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