{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:23:15Z","timestamp":1791411795820,"version":"4.3.3"},"reference-count":61,"publisher":"American Physiological Society","issue":"2","funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F30DK107194"],"award-info":[{"award-number":["F30DK107194"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F31HL151264"],"award-info":[{"award-number":["F31HL151264"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL173038"],"award-info":[{"award-number":["R01HL173038"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL117684"],"award-info":[{"award-number":["U01HL117684"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Function"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:p>\n                    Sickle cell nephropathy (SCN) significantly shortens the life expectancy of patients with sickle cell disease (SCD). We previously reported that endothelin-1 (ET-1) and endothelin A receptor (ET\n                    <jats:sub>A<\/jats:sub>\n                    ) are upregulated in SCN, and ET\n                    <jats:sub>A<\/jats:sub>\n                    antagonism mitigates SCN early in the disease progression in a humanized mouse model of SCD. We hypothesized that endothelium-derived ET-1 mediates the progression of SCN and T cell inflammation in the kidney of SCD mice. To test this hypothesis, we first used allogenic bone marrow transplantation from humanized sickle cell mice (HbSS) into endothelial-derived ET-1 knockout (VEET KO) mice, revealing that endothelial-derived ET-1 mitigates SCN and regulates the renal inflammatory response and T cell infiltration. Second, using young (4\u20135 mo old) and middle-aged (10\u201315 mo old) HbSS mice lacking endothelial-specific ET-1 (HbSS-VEET KO), we found a temporal maintenance of glomerular filtration rate, reduced infiltration of T cells to the kidney, and reduced progression of SCN. Furthermore, 2-wk ET\n                    <jats:sub>A<\/jats:sub>\n                    antagonism in middle-aged HbSS mice reduced infiltration of T cells. Finally, flow cytometric analyses revealed blunting of kidney T helper 17 (T\n                    <jats:sub>H<\/jats:sub>\n                    17) cells without a change in kidney T regulatory cells in HbSS-VEET KO mice, suggesting T cell subset-specific regulation by endothelial-derived ET-1 signaling. In vitro studies showed that ET\n                    <jats:sub>A<\/jats:sub>\n                    antagonism directly inhibits T\n                    <jats:sub>H<\/jats:sub>\n                    17 polarization and IL-17A production, suggesting that in established sickle cell disease, the ET\n                    <jats:sub>A<\/jats:sub>\n                    receptor-T\n                    <jats:sub>H<\/jats:sub>\n                    17 cell axis may play a key role in maintenance of fibrosis in SCN. Taken together, these data indicate that endothelial-derived ET-1 mediates the progression of SCN and strengthens the rationale for targeting ET-1 signaling as a new therapeutic approach.\n                  <\/jats:p>","DOI":"10.1152\/function.001.2026","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T20:00:36Z","timestamp":1774296036000},"source":"Crossref","is-referenced-by-count":1,"title":["Endothelium-derived endothelin-1 mediates sickle cell nephropathy"],"prefix":"10.1152","volume":"7","author":[{"given":"Malgorzata","family":"Kasztan","sequence":"first","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]},{"name":"University of Alabama at Birmingham","place":["United States"]},{"name":"University of North Carolina at Chapel Hill","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick A.","family":"Molina","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon M.","family":"Fox","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Saurage","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson C.","family":"Colson","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Pollock","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1956-0449","authenticated-orcid":false,"given":"Jennifer S.","family":"Pollock","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2015.8"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24557"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23683"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-022-00540-9"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(89)90011-4"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2015.02.002"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfi111"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.7.2594"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.7.2551"},{"key":"B10","first-page":"401","volume":"90","author":"Lapoum\u00e9roulie C","year":"2005","journal-title":"Haematologica"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016070711"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1042\/CS20190215"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1124\/pr.115.011833"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2730"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010050536"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.020"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501831"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aba4163"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.102"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2017.112"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2016.03.008"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nature15367"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.156869"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-02-004812"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5339.873"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018028878"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.138701"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-04-1251"},{"key":"B29","unstructured":"Molina PA. 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