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ET\u20101 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\u20101 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis\u2010induced acute cardiorenal injuries. To analyse the role of ET\u20101 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non\u2010treated group, CLP\u2010treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5\u2009mg\/kg, respectively), and sham\u2010operated 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\u20101, IL\u20106, and lactate were measured. The expression of TNF\u2010\u03b1, p38, Klotho, and caspase\u20103 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET\u20101, IL\u20106, and lactate, as well as an imbalance in oxidant\/antioxidant activities, elevated expression of TNF\u2010\u03b1, p38, caspase\u20103 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\u2010\u03b1 and caspase\u20103. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE\u2010i) phosphoramidon, are promising agents against sepsis\u2010induced organ damage. This was evident in their cardiorenal protective effects, up\u2010regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.<\/jats:p>","DOI":"10.1111\/1440-1681.70042","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:09:37Z","timestamp":1744675777000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Endothelin System Blockade Extenuates Sepsis\u2010Induced Acute Heart and Kidney Injuries via Modulating <scp>ET\u20101\/Klotho\/p38\u2010MAPK<\/scp>"],"prefix":"10.1111","volume":"52","author":[{"given":"Alaa","family":"Al\u2010kadi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Deraya University  Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliaa F.","family":"Anter","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Minia University  Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remon Roshdy","family":"Rofaeil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Deraya University  Minia Egypt"},{"name":"Department of Medical Pharmacology Faculty of Medicine, Minia University  Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2179-8002","authenticated-orcid":false,"given":"Mohamed M.","family":"Sayed\u2010Ahmed","sequence":"additional","affiliation":[{"name":"Pharmacology and Experimental Oncology Unit National Cancer Institute, Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Mohamed Naguib Abdel","family":"Hafez","sequence":"additional","affiliation":[{"name":"Histology and Cell Biology Department Minia University, Faculty of Medicine, Minia University Faculty of Medicine  Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9875-6399","authenticated-orcid":false,"given":"Al\u2010Shaimaa F.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy, Minia University  Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32989-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2020.100767"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k4891"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2019.05.026"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501017"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201910-1911TR"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.12105"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-014-0310-1"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajhp\/zxab393"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-021-00489-1"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001414"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/diseases6020038"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/01902140701884430"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112592"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.102117"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9040398"},{"issue":"7","key":"e_1_2_10_19_1","first-page":"1627","article-title":"Assessment of Serum Endothelin\u20101 Levels in Rat Appendicitis Model and the Effects of Bosentan","volume":"21","author":"Sarsu S.","year":"2017","journal-title":"European Review for Medical and Pharmacological Sciences"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.36295\/ASRO.2020.23411"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/0960327115583363"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2011.01.001"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.21608\/jabps.2019.19876.1061"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.12718"},{"key":"e_1_2_10_25_1","unstructured":"A.Al\u2010Kadi M.El\u2010Daly N. 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