circRNA-PTPN4 mediated regulation of FOXO3 and ZO-1 expression: implications for blood–brain barrier integrity and cognitive function in uremic encephalopathy

IF 5.3 2区医学 Q2 CELL BIOLOGY Cell Biology and Toxicology Pub Date : 2024-04-17 DOI:10.1007/s10565-024-09865-6

Yuhan Liu, Yanling Qin, Yanning Zhang

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Abstract

Uremic encephalopathy (UE) poses a significant challenge in neurology, leading to the need to investigate the involvement of non-coding RNA (ncRNA) in its development. This study employed ncRNA-seq and RNA-seq approaches to identify fundamental ncRNAs, specifically circRNA and miRNA, in the pathogenesis of UE using a mouse model. In vitro and in vivo experiments were conducted to explore the circRNA-PTPN4/miR-301a-3p/FOXO3 axis and its effects on blood–brain barrier (BBB) function and cognitive abilities. The research revealed that circRNA-PTPN4 binds to and inhibits miR-301a-3p, leading to an increase in FOXO3 expression. This upregulation results in alterations in the transcriptional regulation of ZO-1, affecting the permeability of human brain microvascular endothelial cells (HBMECs). The axis also influences the growth, proliferation, and migration of HBMECs. Mice with UE exhibited cognitive deficits, which were reversed by overexpression of circRNA-PTPN4, whereas silencing FOXO3 exacerbated these deficits. Furthermore, the uremic mice showed neuronal loss, inflammation, and dysfunction in the BBB, with the expression of circRNA-PTPN4 demonstrating therapeutic effects. In conclusion, circRNA-PTPN4 plays a role in promoting FOXO3 expression by sequestering miR-301a-3p, ultimately leading to the upregulation of ZO-1 expression and restoration of BBB function in mice with UE. This process contributes to the restoration of cognitive abilities.

Graphical Abstract

1. The circRNA-PTPN4/miR-301a-3p/FOXO3 axis is identified as a key regulator of blood–brain barrier integrity and cognitive function in uremic encephalopathy.

2. circRNA-PTPN4 sequestration of miR-301a-3p enhances FOXO3 expression, leading to upregulation of ZO-1 and improved endothelial permeability.

3. Overexpression of circRNA-PTPN4 in uremic mice restores cognitive abilities and reduces neuronal loss and inflammatory infiltration.

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circRNA-PTPN4 介导的 FOXO3 和 ZO-1 表达调控：对尿毒症脑病患者血脑屏障完整性和认知功能的影响

尿毒症脑病（UE）给神经病学带来了巨大挑战，因此需要研究非编码 RNA（ncRNA）在其发病过程中的参与。本研究采用ncRNA-seq和RNA-seq方法，以小鼠模型为基础，鉴定了UE发病机制中的基本ncRNA，特别是circRNA和miRNA。研究人员通过体外和体内实验探讨了circRNA-PTPN4/miR-301a-3p/FOXO3轴及其对血脑屏障（BBB）功能和认知能力的影响。研究发现，circRNA-PTPN4与miR-301a-3p结合并抑制miR-301a-3p，导致FOXO3表达增加。这种上调导致 ZO-1 的转录调控发生改变，从而影响人脑微血管内皮细胞（HBMECs）的通透性。该轴还会影响 HBMECs 的生长、增殖和迁移。尿毒症小鼠表现出认知缺陷，过表达 circRNA-PTPN4 可逆转这些缺陷，而沉默 FOXO3 则会加剧这些缺陷。此外，尿毒症小鼠表现出神经元缺失、炎症和BBB功能障碍，而circRNA-PTPN4的表达则显示出治疗效果。总之，circRNA-PTPN4通过封存miR-301a-3p，在促进FOXO3表达方面发挥作用，最终导致ZO-1表达上调，恢复尿毒症小鼠的BBB功能。这一过程有助于认知能力的恢复。circRNA-PTPN4/miR-301a-3p/FOXO3 轴被认为是尿毒症脑病中血脑屏障完整性和认知功能的关键调节因子。circRNA-PTPN4 封闭 miR-301a-3p 可增强 FOXO3 的表达，导致 ZO-1 上调并改善内皮通透性。 3. 在尿毒症小鼠中过表达 circRNA-PTPN4 可恢复认知能力并减少神经元损失和炎症浸润。

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来源期刊

Cell Biology and Toxicology 生物-毒理学

CiteScore

9.90

自引率

4.90%

发文量

101

审稿时长

>12 weeks

期刊介绍： Cell Biology and Toxicology (CBT) is an international journal focused on clinical and translational research with an emphasis on molecular and cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular pharmacology and toxicology. CBT has a disease-specific scope prioritizing publications on gene and protein-based regulation, intracellular signaling pathway dysfunction, cell type-specific function, and systems in biomedicine in drug discovery and development. CBT publishes original articles with outstanding, innovative and significant findings, important reviews on recent research advances and issues of high current interest, opinion articles of leading edge science, and rapid communication or reports, on molecular mechanisms and therapies in diseases.