Wnt/β-catenin signaling inhibits oxidative stress-induced ferroptosis to improve interstitial cystitis/bladder pain syndrome by reducing NF-κB

IF 4.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Weilin Fang , Xin Song , Hailong Li , Fanguo Meng , Tingting Lv , Jin Huang , Xiang Ji , Jianwei Lv , Zhikang Cai , Zhong Wang
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引用次数: 0

Abstract

Background

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a bladder syndrome of unknown etiology. Reactive oxygen species (ROS) plays a major role in ferroptosis and bladder dysfunction of IC/BPS, while the role of ferroptosis in IC/BPS progression is still unclear. This study aims to investigate the role and mechanism of ROS-induced ferroptosis in IC/BPS using cell and rat model.

Methods

We collected IC/BPS patient bladder tissue samples and established a LPS-induced IC/BPS rat model (LRM). The level of oxidative stress and ferroptosis in IC/BPS patients and LRM rats was analyzed. Function and regulatory mechanism of ferroptosis in IC/BPS were explored by in vitro and in vivo experiments.

Results

The patients with IC/BPS showed mast cells and inflammatory cells infiltration in bladder epithelial tissues. Expression of NRF2 was up-regulated, and GPX4 was decreased in IC/BPS patients compared with normal tissues. IC model cells underwent oxidative stress, which induced ferroptosis. These above results were validated in LRM rat models, and inhibition of ferroptosis ameliorated bladder dysfunction in LRM rats. Wnt/β-catenin signaling was deactivated in IC/BPS patients and animals, and activation of Wnt/β-catenin signaling reduced cellular free radical production, thereby inhibited ferroptosis in IC model cells. Mechanistically, the Wnt/β-catenin signaling pathway inhibited oxidative stress-induced ferroptosis by down-regulating NF-κB, thus contributing to recover IC/BPS both in vitro and in vivo.

Conclusions

We demonstrate for the first time that oxidative stress-induced ferroptosis plays an important role in the pathology of IC/BPS. Mechanistically, the Wnt/β-catenin signaling suppressed oxidative stress-induced ferroptosis by down-regulating NF-κB to improve bladder injury in IC/BPS.

Wnt/β-catenin信号通过减少NF-κB抑制氧化应激诱导的铁氧化,从而改善间质性膀胱炎/膀胱疼痛综合征。
背景:间质性膀胱炎/膀胱疼痛综合征(IC/BPS间质性膀胱炎/膀胱疼痛综合征(IC/BPS)是一种病因不明的膀胱综合征。活性氧(ROS)在IC/BPS的铁氧化和膀胱功能障碍中起着重要作用,而铁氧化在IC/BPS进展中的作用仍不清楚。本研究旨在利用细胞和大鼠模型研究ROS诱导的铁氧化在IC/BPS中的作用和机制:方法:我们收集了IC/BPS患者的膀胱组织样本,并建立了LPS诱导的IC/BPS大鼠模型(LRM)。方法:我们采集了IC/BPS患者的膀胱组织样本,并建立了LPS诱导的IC/BPS大鼠模型(LRM),分析了IC/BPS患者和LRM大鼠体内氧化应激和铁氧化的表达。通过体外和体内实验探讨了铁氧化在 IC/BPS 中的功能和调控机制:结果:IC/BPS 患者的膀胱上皮组织有肥大细胞和炎性细胞浸润。与正常组织相比,IC/BPS 患者体内 NRF2 表达上调,GPX4 表达下降。IC 模型细胞发生氧化应激,从而诱导铁变态反应。上述结果在 LRM 大鼠模型中得到了验证,抑制铁蛋白沉积可改善 LRM 大鼠的膀胱功能障碍。Wnt/β-catenin信号在IC/BPS患者和动物中失活,而激活Wnt/β-catenin信号可减少细胞自由基的产生,从而抑制IC模型细胞的铁蛋白沉积。从机制上讲,Wnt/β-catenin 信号通路通过下调 NF-κB 抑制了氧化应激诱导的铁卟啉沉积,从而有助于体外和体内 IC/BPS 的康复:结论:我们首次证明了氧化应激诱导的铁蛋白沉积在 IC/BPS 的病理过程中起着重要作用。从机理上讲,Wnt/β-catenin 信号通过下调 NF-κB 抑制了氧化应激诱导的铁蛋白沉积,从而改善了 IC/BPS 的膀胱损伤。
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来源期刊
CiteScore
10.00
自引率
2.00%
发文量
151
审稿时长
44 days
期刊介绍: BBA Molecular Cell Research focuses on understanding the mechanisms of cellular processes at the molecular level. These include aspects of cellular signaling, signal transduction, cell cycle, apoptosis, intracellular trafficking, secretory and endocytic pathways, biogenesis of cell organelles, cytoskeletal structures, cellular interactions, cell/tissue differentiation and cellular enzymology. Also included are studies at the interface between Cell Biology and Biophysics which apply for example novel imaging methods for characterizing cellular processes.
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