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METTL3 mediated m6A modification of HKDC1 promotes renal injury and inflammation in lead nephropathy via binding to ATPB

ABSTRACT: Environmental and industrial Pb exposure poses a major public health problem. Acute exposure to high Pb concentrations can result in renal injury. Here, we reveal that N6-methyladenosine (m6A) RNA methylation is significantly upregulated in lead nephropathy and is mainly mediated by the methyltransferase METTL3. Functionally, METTL3 knockout in renal tubular epithelial cells or AAV9 mediated METTL3 silencing alleviated renal injury and inflammatory response induced by lead acetate. METTL3 silencing in HK2 cells reduces m6A RNA methylation and inflammatory responses following lead acetate treatment. We identified hexokinase domain-containing 1 (HKDC1), which is known to function in the glycolytic pathway, as a direct METTL3 target. Moreover, HKDC1 was upregulated at both mRNA and protein levels after lead acetate treatment, promoting kidney injury and inflammation. Mechanistically, HKDC1 binds to ATPB and antagonises the ubiquitinase Murf1, thereby increasing ATPB expression. Therefore, excessive ATP is generated to activate the NF-κB signalling pathway and promote renal inflammation. We further confirmed that STM2457, a novel inhibitor of METTL3, protects against renal injury and inflammation induced by lead acetate. Collectively, our study demonstrates that the METTL3/HKDC1 axis is a potential target for the treatment of lead nephropathy, and STM2457 is expected to be a protective agent against renal injury caused by lead acetate.

ORGANISM(S): Mus musculus

PROVIDER: GSE288167 | GEO | 2025/06/18

REPOSITORIES: GEO

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METTL3 mediated m6A modification of HKDC1 promotes renal injury and inflammation in lead nephropathy via binding to ATPB

Project description:METTL3 mediated m6A modification of HKDC1 promotes renal injury and inflammation in lead nephropathy via binding to ATPB

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Project description:The role of N6-methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterised the role of N6-adenosine-methyltransferase METTL3, whose expression is elevated in renal tubules in different acute kidney injury (AKI) models as well as in human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated renal inflammation and programmed cell death in TECs in response to stimulation by tumor necrosis factor alpha (TNF-α), cisplatin, and lipopolysaccharide (LPS), whereas METTL3 overexpression had the opposite effects. Conditional knockout (cKO) of METTL3 from mouse kidneys attenuated cisplatin- and ischemic/reperfusion (I/R)-induced renal dysfunction, injury, and inflammation. Moreover, TAB3 was identified as a target of METTL3 by m6A methylated RNA immunoprecipitation sequencing and RNA sequencing. The stability of TAB3 was increased through binding of IGF2BP2 to its m6A-modified stop codon regions. The pro-inflammatory effects of TAB3 were then explored both in vivo and in vitro. Adeno-associated virus 9 (AAV9)-mediated METTL3 silencing attenuated renal injury and inflammation in cisplatin- and LPS-induced AKI mouse models. We further identified Cpd-564 as a METTL3 inhibitor that had better protective effects against cisplatin- and I/R-induced renal injury and inflammation than S-adenosyl-L-homocysteine, a previously-identified METTL3 inhibitor. Collectively, METTL3 promoted m6A modification of TAB3 and enhanced its stability via IGF2BP2-dependent mechanisms. Both pharmacological and genetic inhibition of METTL3 attenuated renal injury and inflammation, suggesting that the METTL3/TAB3 axis is a potential target for treatment of AKI.

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RNA-seq of human breast cancer cell line MDA-MB-231 treated with STM2457 against untreated controls

Project description:Here, we aim to investigate if catalytic inhibition of the m6A methyltransferase METTL3 by the small-molecule STM2457 may be a viable treatment option for TNBC.

2023-12-18 | E-MTAB-13184 | biostudies-arrayexpress

Profile of N6-methyladenosine of Pb-exposed neurons presents epitranscriptomic alterations in Pi3K-AKT pathway-associated genes

Project description:Lead (Pb) is a pervasive heavy metal with multi-organ toxicity. However, the molecular mechanisms of Pb-induced neurotoxicity are not fully understood. The dynamics of N6-methylademine (m6A) is an emerging regulatory mechanism for gene expression, which is closely related to nervous system diseases. To elucidate the association between m6A modification and Pb-mediated neurotoxicity, primary hippocampal neurons exposed to 5 μM Pb for 48 h were used as the paradigm neurotoxic model in this study. According to the results, Pb exposure reprogrammed the transcription spectrum. Simultaneously, Pb exposure remodeled the transcriptome-wide distribution of m6A while disrupting the overall level of m6A in cellular transcripts. United analysis of MeRIP-Seq and RNA-Seq was applied to further identify the core genes whose expression levels are regulated by m6A in the process of lead-induced nerve injury. GO and KEGG analysis unveiled that the modified transcripts were overrepresented by the PI3K-AKT pathway. Mechanically, we elucidated the regulatory role of the methyltransferase like3 (METTL3) in the process of lead-induced neurotoxicity and the downregulation of the PI3K-AKT pathway. In conclusion, our novel findings shed new light on the functional roles of m6A modification in the expressional alternations of downstream transcripts caused by lead, providing an innovative molecular basis to explain Pb neurotoxicity.

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Inhibition of METTL3 protect against traumatic brain injury

Project description:Researchers recently identified STM2457 as a first-in-class catalytic inhibitor of METTL3 and observed a promising therapeutic effect on acute myeloid leukemia. However, it is crucial to note that the existence of the blood-brain barrier (BBB) limit the efficiency of drugs entering the brain to a large extent. In order to effectively deliver METTL3 inhibitor STM2457 to the brain, we generated RVG29 (a BBB-penetrating peptide)-based modified nanoparticle system loaded with STM2457 (abbreviated as RVG-nSTM system) that targets the brain. Specifically, a mixture of STM2457, PLGA20K-mPEG2K, and PLGA20K-PEG5K-MAL was used to prepare nSTM, which was further modified with RVG29 peptide. We investigated the impact of RVG-nSTM on neuroinflammation post-TBI in mice. We performed a total RNA-seq analysis, and observed distinct gene distributions on the volcano plot. A Venn diagram revealed that 3385 genes were differentially expressed in the TBI group compared to the sham group, and treatment with RVG-nSTM reversed the expression of 1941 of these genes . The subsequent GO and KEGG analyses showed that these 1941 genes were primarily enriched in the context of inflammatory response and inflammation-related pathways. These findings were further corroborated by the observation that RVG-nSTM treatment leads to a substantial reversal of the hyperactive microglial states that are induced by TBI . Above all, RVG-nSTM could be a promising agent for the treatment of neuroinflammation after acute brain injury.

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The METTL3 RNA methyltransferase regulates gene expression in castrate resistant LNCaP:C42 prostate cancer cells

Project description:RNA sequencing was used to determine the effect of the STM2457 METTL3 inhibitor on prostate cancer cell gene expression.

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Project description:RNA sequencing was used to determine the effect of the STM2457 METTL3 inhibitor on prostate cancer cell gene expression.

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Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

Project description:Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb-/-) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb-/- kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb-/- kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngalhigh versus Ngallow kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb-/- mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction. Gene expression was measured in control, mild, moderate and severely hydronephrotic megabladder mouse kidneys. A total of 6 control kidneys were compared to 18 mutant kidneys from age-matched male animals.

2013-06-18 | E-GEOD-48041 | biostudies-arrayexpress

Expression data from OVE26 diabetic mouse kidney

Project description:OVE26 mouse was chosen to study the progressive changes in renal gene expression because it displays the most advanced albuminuria mouse models that assembles advanced human diabetic nephropathy. OVE26 mice induce inflammatory gene expression changes consistent with advanced renal disease, associated with severe albuminuria and not reported in any other diabetic models. They provide the first opportunity in a model of diabetic nephropathy to assess the effect of induction of inflammatory proteins that have been implicated in renal injury. Microarray expression was performed on whole kidney from control and diabetic mice at 2, 4 and 8 months of age and validated by rtPCR, in situ hybridization or immunohistochemistry.

2010-04-06 | E-GEOD-20636 | biostudies-arrayexpress

Whole blood gene expression in female Balb/c mice following 2-week Pb exposure and subsequent 2-week recovery period

Project description:Background: Current evidence indicates that even low-level lead (Pb) exposure can have detrimental effects, especially in children. We tested the hypothesis that Pb exposure alters gene expression patterns in peripheral blood cells and that these changes reflect dose-specific alterations in the activity of particular pathways. Methodology/Principal Finding: Using Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in the peripheral blood of female Balb/c mice following exposure to per os lead acetate trihydrate or plain drinking water for two weeks and after a two-week recovery period. Data sets were RMA-normalized and dose-specific signatures were generated using established methods of supervised classification and binary regression. Pathway activity was analyzed using the ScoreSignatures module from GenePattern. Conclusions/Significance: The low-level Pb signature was 93% sensitive and 100% specific in classifying samples a leave-one-out crossvalidation. The high-level Pb signature demonstrated 100% sensitivity and specificity in the leave-one-out crossvalidation. These two signatures exhibited dose-specificity in their ability to predict Pb exposure and had little overlap in terms of constituent genes. The signatures also seemed to reflect current levels of Pb exposure rather than past exposure. Finally, the two doses showed differential activation of cellular pathways. Low-level Pb exposure increased activity of the interferon-gamma pathway, whereas high-level Pb exposure increased activity of the E2F1 pathway. We isolate total RNA from 72 mouse whole blood samples. These included samples following a 2-week exposure to lead acetate trihydrate (untreated controls = 7; Low Pb 5ug/mL drinking water = 15; High Pb 50ug/mL drinking water = 15) and additional samples following a 2-week recovery period with plain drinking water (untreated controls = 7; Low Pb group = 15; High Pb group = 13).

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