METTL3 Potentiates M2 Macrophage‐Driven MMT to Aggravate Renal Allograft Fibrosis via the TGF‐β1/Smad3 Pathway

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Abstract METTL3, a key enzyme in N6‐methyladenosine (m6A) modification, plays crucial role the progression of renal fibrosis, particularly chronic active allograft rejection (CAR). This study explored mechanisms by which METTL3 promotes focusing on its macrophage‐to‐myofibroblast transition (MMT). Using comprehensive experimental approach, including TGF‐β1‐induced MMT cell models, conditional knockout (METTL3 KO) mice, and biopsy samples from patients with CAR, investigates involvement METTL3/Smad3 axis driving fibrosis during episodes CAR. We found that elevated m6A modification levels strongly correlated enhanced increased fibrotic severity. significantly Smad3, decreased Smad3 expression, inhibited M2‐driven MMT. knockdown siRNA (siSmad3) further MMT, while overexpression rescued inhibitory effects silencing, restoring tissue damage. Additionally, inhibitor STM2457 effectively reversed alleviated damage These findings highlight enhances CAR promoting TGF‐β1/Smad3 axis, suggesting is promising therapeutic target for mitigating

Language: Английский

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Deletion of Pyruvate Carboxylase in Tubular Epithelial Cell Promotes Renal Fibrosis by Regulating SQOR/cGAS/STING‐Mediated Glycolysis

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Abstract Renal fibrosis is a common pathway involved in the progression of various chronic kidney diseases to end‐stage renal disease. Recent studies show that mitochondrial injury tubular epithelial cells (RTECs) crucial pathological foundation for fibrosis. However, underlying regulatory mechanisms remain unclear. Pyruvate carboxylase (PC) catalytic enzyme located within mitochondria intricately linked with damage and metabolism. In present study, downregulation PC fibrotic animal human samples demonstrated. proximal tubule–specific Pcx gene knockout mice ( cKO ) has significant interstitial compared control mice, heightened expression extracellular matrix molecules. This further demonstrated stable knock‐out RTEC line. Mechanistically, deficiency reduces its interaction sulfide:quinone oxidoreductase (SQOR), increasing ubiquitination degradation SQOR. leads morphological functional disruption, increased mtDNA release, activation cGAS‐STING pathway, elevated glycolysis levels, ultimately, promotes study investigates molecular through which induces metabolic reprogramming RTECs. provides novel theoretical potential therapeutic targets pathogenesis treatment

Language: Английский

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STING Facilitates Vascular Calcification via p‐STAT1/NLRP3 Signal

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(7)

Published: April 7, 2025

ABSTRACT Vascular calcification is an independent predictor of cardiovascular mortality in patients with chronic kidney disease (CKD), yet no approved treatment exists. The cGAS‐STING signaling participates various diseases. Notably, DNA damage, important regulator vascular calcification, activates the signaling. However, it remains poorly understood whether STING regulates under CKD conditions. In current study, we showed that expression was elevated during calcification. knockdown or pharmacological inhibition decreased calcium deposits smooth muscle cells and human arterial rings, while its activation exacerbated Furthermore, knockout mice exhibited reduced aortic RNA sequencing analysis suggested STAT1 pathway may mediate STING‐induced phosphorylated (p‐STAT1) levels, p‐STAT1 mitigated VSMCs tissues. Additionally, downregulated NLRP3 expression, inhibiting further attenuated VSMC indicating accelerates via activation. Altogether, our study highlights STING/p‐STAT1/NLRP3 axis as a key mediator suggesting targeting represent promising therapeutic approach for patients.

Language: Английский

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NLRX1 and STING alleviate renal ischemia-reperfusion injury by regulating LC3 lipidation during mitophagy

Experimental Cell Research, Journal Year: 2024, Volume and Issue: 443(1), P. 114323 - 114323

Published: Nov. 1, 2024

Language: Английский

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m6A modification in non-coding RNAs: Mechanisms and potential therapeutic implications in fibrosis

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 179, P. 117331 - 117331

Published: Aug. 26, 2024

N6-methyladenosine (m

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N6-methyladenosine regulates metabolic remodeling in kidney aging through transcriptional regulator GLIS1

BMC Biology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Dec. 31, 2024

Age-related kidney impairment, characterized by tubular epithelial cell senescence and renal fibrosis, poses a significant global public health threat. Although N6-methyladenosine (m6A) methylation is implicated in various pathological processes, its regulatory mechanism aging remains unclear. An m6A-mRNA epitranscriptomic microarray was performed to identify genes with abnormal m6A modifications aged human tissues. Histological, immunohistochemical, immunofluorescent staining, western blot, RT-qPCR were employed examine the biological functions of targeted methyltransferases both vivo vitro. RNA immunoprecipitation, chromatin ribosomal luciferase reporter assays used investigate specific interactions between methyltransferases, genes, their downstream signals. Significantly lower modification levels observed GLIS1, identified as "metabolic remodeling factor," showed significantly reduced protein modifications. The downregulation GLIS1 induced fibrosis shifting metabolic from fatty acid oxidation (FAO) glycolysis. Additionally, methylated mRNA regulated expression METTL3 YTHDF1. Silencing METTL3/YTHDF1 weakened translation disrupted balance FAO Our findings suggest that activated YTHDF1-dependent manner, leads regulating shift This provides promising therapeutic target for aging.

Language: Английский

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mRNA Modification and Mechanisms of Kidney Fibrosis

Journal of the American Society of Nephrology, Journal Year: 2024, Volume and Issue: 35(10), P. 1297 - 1299

Published: Aug. 21, 2024

Division of CKD Pathophysiology, Graduate School Medicine, The University Tokyo, Japan Correspondence: Prof. Reiko Inagi, email: [email protected] See related article, "METTL3-Mediated N6-Methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis," on pages XXX–XXX.

Language: Английский

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Mettl3-Mediated Cep170 M6a Modifications in Spindle Orientation and Esophageal Cancer Cell Proliferation

Published: Jan. 1, 2024

Language: Английский

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CXCL5 inhibition ameliorates acute kidney injury and prevents the progression from acute kidney injury to chronic kidney disease

Clinical Science, Journal Year: 2024, Volume and Issue: 138(22), P. 1451 - 1466

Published: Nov. 1, 2024

Abstract Acute kidney injury (AKI) increases the risk of chronic disease (CKD). CXC motif chemokine ligand 5 (CXCL5) is up-regulated in diseases. We aimed to investigate direct effect CXCL5 on pathology AKI. Serum and renal expression were increased animals with ischemia–reperfusion or unilateral ureteral obstruction. CXCL5-knockout mice exhibited reduced systemic oxidative stress preserved function acute phases AKI, as evidenced by reductions serum BUN creatinine levels, urinary albumin-to-creatinine ratio, kidney-to-body weight ratio. improved AKI-induced tubular fibrosis, macrophage infiltration, NADPH oxidase inflammatory fibrotic proteins. activated p47 up-regulate ROS generation induce cellular damages through CXCR2. knockdown exerted antioxidative, anti-inflammatory, anti-fibrotic, anti-apoptotic effects hypoxia-reoxygenation-stimulated proximal epithelial cells. Clinical data indicated elevated circulating CKD patients, was correlated fibrosis decreased estimated glomerular filtration rate. Altogether, levels experimental AKI clinical CKD, vivo vitro inhibition may reduce prevent subsequent progression from CKD.

Language: Английский

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SREBP1c‐Mediated Transcriptional Repression of YME1L1 Contributes to Acute Kidney Injury by Inducing Mitochondrial Dysfunction in Tubular Epithelial Cells

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract Acute kidney injury (AKI) is a prevalent clinical syndrome with high morbidity and mortality. Accumulating studies suggest mitochondrial dysfunction as the typical characteristics key process of AKI, but underlying mechanism remains elusive. The YME1‐like 1 (YME1L1) ATPase, an inner membrane protein, screened identified to be downregulated in renal tubular epithelial cells various mouse models patients AKI. Dramatically, restoration YME1L1 expression significantly alleviates cisplatin‐induced AKI subsequent chronic disease (CKD) through attenuating via maintaining optic atrophy (OPA1)‐mediated energy metabolism homeostasis. Mechanistically, upregulated sterol regulatory element binding transcription factor 1c (SREBP1c) demonstrated responsible for cisplatin‐mediated transcriptional inhibition directly its promoter region. Moreover, methyltransferase‐like 3 (METTL3)‐mediated m6A modification enhances SREBP1c mRNA stability, thereby upregulating expression. Notably, both depletion tubule‐specific overexpression markedly ameliorate transition CKD. Taken together, these findings that METTL3‐mediated upregulation contributes progression CKD disrupting transcriptionally suppressing YME1L1. Targeting SREBP1c/YME1L1 signaling may serve novel therapeutic strategy against

Language: Английский

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