{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:43:14Z","timestamp":1793256194098,"version":"4.5.0"},"reference-count":59,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"675","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,12,14]]},"abstract":"<jats:p>\n            Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular\/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6C\n            <jats:sup>high<\/jats:sup>\n            monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A\/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6C\n            <jats:sup>high<\/jats:sup>\n            monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C\n            <jats:sup>low<\/jats:sup>\n            monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.abf5074","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T18:59:23Z","timestamp":1671044363000},"source":"Crossref","is-referenced-by-count":34,"title":["Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6800-6749","authenticated-orcid":true,"given":"Alicja","family":"Czopek","sequence":"first","affiliation":[{"name":"Edinburgh Kidney, University\/BHF Centre of Research Excellence, University of Edinburgh, Queen\u2019s Medical Research Institute, 47 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Queen\u2019s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK."},{"name":"Department of Renal Medicine, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-4376","authenticated-orcid":true,"given":"Jessica R.","family":"Ivy","sequence":"additional","affiliation":[{"name":"Edinburgh Kidney, University\/BHF Centre of Research Excellence, University of Edinburgh, Queen\u2019s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq E.","family":"Farrah","sequence":"additional","affiliation":[{"name":"Edinburgh Kidney, University\/BHF Centre of Research Excellence, University of Edinburgh, Queen\u2019s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK."},{"name":"Department of Renal Medicine, Royal Infirmary of 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UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-1756","authenticated-orcid":true,"given":"David J.","family":"Webb","sequence":"additional","affiliation":[{"name":"Edinburgh Kidney, University\/BHF Centre of Research Excellence, University of Edinburgh, Queen\u2019s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6062-5905","authenticated-orcid":true,"given":"Pierre-Louis","family":"Tharaux","sequence":"additional","affiliation":[{"name":"Paris Cardiovascular Research Centre (PARCC), Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), 75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3179-0661","authenticated-orcid":true,"given":"David C.","family":"Kluth","sequence":"additional","affiliation":[{"name":"Edinburgh 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