Endothelin System Blockade Extenuates Sepsis-Induced Acute Heart and Kidney Injuries via Modulating ET-1/Klotho/p38-MAPK

IF 2.9 4区 医学 Q2 Medicine
Alaa Al-kadi, Aliaa F. Anter, Remon Roshdy Rofaeil, Mohamed M. Sayed-Ahmed, Sara Mohamed Naguib Abdel Hafez, Al-Shaimaa F. Ahmed
{"title":"Endothelin System Blockade Extenuates Sepsis-Induced Acute Heart and Kidney Injuries via Modulating ET-1/Klotho/p38-MAPK","authors":"Alaa Al-kadi,&nbsp;Aliaa F. Anter,&nbsp;Remon Roshdy Rofaeil,&nbsp;Mohamed M. Sayed-Ahmed,&nbsp;Sara Mohamed Naguib Abdel Hafez,&nbsp;Al-Shaimaa F. Ahmed","doi":"10.1111/1440-1681.70042","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Sepsis-induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin-1 (ET-1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET-1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET-1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis-induced acute cardiorenal injuries. To analyse the role of ET-1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non-treated group, CLP-treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham-operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET-1, IL-6, and lactate were measured. The expression of TNF-α, p38, Klotho, and caspase-3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET-1, IL-6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF-α and caspase-3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE-i) phosphoramidon, are promising agents against sepsis-induced organ damage. This was evident in their cardiorenal protective effects, up-regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.</p>\n </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Experimental Pharmacology and Physiology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/1440-1681.70042","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

Abstract

Sepsis-induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin-1 (ET-1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET-1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET-1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis-induced acute cardiorenal injuries. To analyse the role of ET-1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non-treated group, CLP-treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham-operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET-1, IL-6, and lactate were measured. The expression of TNF-α, p38, Klotho, and caspase-3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET-1, IL-6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF-α and caspase-3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE-i) phosphoramidon, are promising agents against sepsis-induced organ damage. This was evident in their cardiorenal protective effects, up-regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.

内皮素系统阻断通过调节ET-1/Klotho/p38-MAPK减轻脓毒症诱导的急性心脏和肾脏损伤
脓毒症引起的器官衰竭是一种主要的健康问题,其特征是大量的炎症和氧化应激反应。内皮素-1 (ET-1)是在败血症中表达的具有促凋亡、促炎和氧化作用的肽之一。ET-1在败血症的心脏和肾脏损伤中起作用。因此,本研究旨在从机制上探讨通过阻断ET-1受体或抑制其形成来抑制ET-1信号是否能减轻败血症诱导的急性心肾损伤。为了分析ET-1在脓毒症中的作用,我们使用了脓毒症的盲肠结扎和穿刺(CLP)模型。将实验动物分为5组:CLP未处理组、波生坦、氨布里森坦和磷酰胺处理组(分别为30、5、0.5 mg/kg)和假手术组。除同一组外,进行生存分析生存率、组织病理学评估、心肾功能分析。测定其氧化和抗氧化活性、ET-1、IL-6和乳酸含量。免疫组化法检测TNF-α、p38、Klotho、caspase-3的表达。CLP引起急性心肾损伤、高死亡率、ET-1、IL-6和乳酸水平上调,以及氧化/抗氧化活性失衡,TNF-α、p38、caspase-3表达升高,klotho表达降低。波生坦、氨布里森坦或磷酰胺可改善大鼠存活率,降低炎症和氧化应激参数水平,改善心肾功能和结构,升高组织中GSH和SOD的含量,升高klotho蛋白的表达,降低p38、TNF-α和caspase-3的表达。内皮素受体拮抗剂;波生坦和氨布里森坦,或内皮素转换酶抑制剂(ECE-i)磷酰胺,是治疗败血症诱导的器官损伤的有希望的药物。这在它们的心肾保护作用、klotho的上调、炎症、氧化、细胞凋亡的抑制和抗氧化状态的增强中是明显的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.20
自引率
0.00%
发文量
128
审稿时长
6 months
期刊介绍: Clinical and Experimental Pharmacology and Physiology is an international journal founded in 1974 by Mike Rand, Austin Doyle, John Coghlan and Paul Korner. Our focus is new frontiers in physiology and pharmacology, emphasizing the translation of basic research to clinical practice. We publish original articles, invited reviews and our exciting, cutting-edge Frontiers-in-Research series’.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信