{"title":"Molecular insights into P2X signalling cascades in acute kidney injury.","authors":"Swati Mishra, Vishwadeep Shelke, Neha Dagar, Maciej Lech, Anil Bhanudas Gaikwad","doi":"10.1007/s11302-024-09987-w","DOIUrl":null,"url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes. More importantly, certain P2X receptor subtypes upon activation exacerbate the situation by promoting the release of extracellular ATP. While therapeutic investigations have primarily focused on P2X<sub>4</sub> and P2X<sub>7</sub> subtypes in the context of AKI, while understanding about other subtypes still remains limited. Whilst some P2X antagonists show promising results against different types of kidney diseases, their role in managing AKI remains unexplored. Henceforth, understanding the intricate interplay between P2X receptors and AKI is crucial for developing targeted interventions. This review elucidates the functional alterations of all P2X receptors during normal kidney function and AKI, offering insights into their involvement in AKI. Notably, we have highlighted the current knowledge of P2X receptor antagonists and the possibilities to use them against AKI in the future. Furthermore, the review delves into the pathways influenced by activated P2X receptors during AKI, presenting potential targets for future therapeutic interventions against this critical condition.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"477-486"},"PeriodicalIF":3.0000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377406/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Purinergic Signalling","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11302-024-09987-w","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Acute kidney injury (AKI) is a critical health issue with high mortality and morbidity rates in hospitalized individuals. The complex pathophysiology and underlying health conditions further complicate AKI management. Growing evidence suggests the pivotal role of ion channels in AKI progression, through promoting tubular cell death and altering immune cell functions. Among these channels, P2X purinergic receptors emerge as key players in AKI pathophysiology. P2X receptors gated by adenosine triphosphate (ATP), exhibit increased extracellular levels of ATP during AKI episodes. More importantly, certain P2X receptor subtypes upon activation exacerbate the situation by promoting the release of extracellular ATP. While therapeutic investigations have primarily focused on P2X4 and P2X7 subtypes in the context of AKI, while understanding about other subtypes still remains limited. Whilst some P2X antagonists show promising results against different types of kidney diseases, their role in managing AKI remains unexplored. Henceforth, understanding the intricate interplay between P2X receptors and AKI is crucial for developing targeted interventions. This review elucidates the functional alterations of all P2X receptors during normal kidney function and AKI, offering insights into their involvement in AKI. Notably, we have highlighted the current knowledge of P2X receptor antagonists and the possibilities to use them against AKI in the future. Furthermore, the review delves into the pathways influenced by activated P2X receptors during AKI, presenting potential targets for future therapeutic interventions against this critical condition.
急性肾损伤(AKI)是一个严重的健康问题,住院病人的死亡率和发病率都很高。复杂的病理生理学和潜在的健康状况使急性肾损伤的治疗更加复杂。越来越多的证据表明,离子通道通过促进肾小管细胞死亡和改变免疫细胞功能,在 AKI 进展过程中发挥着关键作用。在这些通道中,P2X嘌呤能受体成为 AKI 病理生理学中的关键角色。受三磷酸腺苷(ATP)门控的 P2X 受体在 AKI 发作时会表现出细胞外 ATP 水平的升高。更重要的是,某些 P2X 受体亚型在激活后会促进细胞外 ATP 的释放,从而加重病情。虽然治疗研究主要集中在 AKI 中的 P2X4 和 P2X7 亚型,但对其他亚型的了解仍然有限。虽然一些 P2X 拮抗剂在治疗不同类型的肾脏疾病方面显示出良好的效果,但它们在控制 AKI 方面的作用仍有待探索。因此,了解 P2X 受体与 AKI 之间错综复杂的相互作用对于开发有针对性的干预措施至关重要。本综述阐明了所有 P2X 受体在正常肾功能和 AKI 期间的功能变化,为它们参与 AKI 提供了见解。值得注意的是,我们强调了目前对 P2X 受体拮抗剂的了解,以及未来使用它们治疗 AKI 的可能性。此外,这篇综述还深入探讨了 AKI 期间受活化的 P2X 受体影响的途径,提出了未来针对这种危急情况进行治疗干预的潜在靶点。
期刊介绍:
Nucleotides and nucleosides are primitive biological molecules that were utilized early in evolution both as intracellular energy sources and as extracellular signalling molecules. ATP was first identified as a neurotransmitter and later as a co-transmitter with all the established neurotransmitters in both peripheral and central nervous systems. Four subtypes of P1 (adenosine) receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of P2Y G protein-coupled receptors have currently been identified. Since P2 receptors were first cloned in the early 1990’s, there is clear evidence for the widespread distribution of both P1 and P2 receptor subtypes in neuronal and non-neuronal cells, including glial, immune, bone, muscle, endothelial, epithelial and endocrine cells.