{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:39:41Z","timestamp":1792143581409,"version":"4.4.0"},"reference-count":74,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T00:00:00Z","timestamp":1738540800000},"content-version":"vor","delay-in-days":63,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01DK115850"],"award-info":[{"award-number":["R01DK115850"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01DK132672"],"award-info":[{"award-number":["R01DK132672"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,3]]},"abstract":"<jats:p>\n                    Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1\u20133 in regulating postischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the 3 PHD isoforms in both mice and humans. Postischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. scRNA-Seq analysis of the postischemic endothelial PHD1, PHD2, and PHD3-deficient (PHD\n                    <jats:sup>TiEC<\/jats:sup>\n                    ) kidney revealed an endothelial hypoxia and glycolysis-related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed proinflammatory EC activation, reducing monocyte-EC interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis\/MCT4 axis.\n                  <\/jats:p>","DOI":"10.1172\/jci176207","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T13:28:17Z","timestamp":1733146097000},"source":"Crossref","is-referenced-by-count":31,"title":["Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis"],"prefix":"10.1172","volume":"135","author":[{"given":"Ratnakar","family":"Tiwari","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajni","family":"Sharma","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganeshkumar","family":"Rajendran","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella S.","family":"Borkowski","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si Young","family":"An","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schonfeld","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0865-1057","authenticated-orcid":true,"given":"Matthew J.","family":"Schipma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-4571","authenticated-orcid":true,"given":"Guillaume","family":"Courbon","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6565-5866","authenticated-orcid":true,"given":"Benjamin R.","family":"Thomson","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9527-2364","authenticated-orcid":true,"given":"Valentin","family":"David","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-5727","authenticated-orcid":true,"given":"Susan E.","family":"Quaggin","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1387-7058","authenticated-orcid":true,"given":"Edward B.","family":"Thorp","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7208-3886","authenticated-orcid":true,"given":"Navdeep S.","family":"Chandel","sequence":"additional","affiliation":[{"name":"Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinelopi P.","family":"Kapitsinou","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute, and"},{"name":"Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."},{"name":"Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-015-3934-7"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32563-2"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.294.7.813"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1214243"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2015.3"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00195.2018"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-023-00752-7"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002312"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1097\/01.mnh.0000441049.98664.6c"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.04.009"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.09.022"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.021"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406026200"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1139\/o02-115"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.021494"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01055-15"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2019050523"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69073"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31772-9"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-174508"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.015"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133267"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.07.038"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.00085.x"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V133806"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.183"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00075.2022"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00580.2005"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-017-0390-x"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2019080832"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-00962-w"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202203069"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316770"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01108-9"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0667-5"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1159\/000514913"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.318805"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.06.003"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.043"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg392"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610415200"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2004.11.022"},{"key":"B43","unstructured":"FDA. FDA Briefing Report: Daprodustat. https:\/\/www.fda.gov\/media\/162521\/download Accessed November 26, 2024"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2113380"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-117812"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00096.2017"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.636944"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00637-6"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105086"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00425.2014"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaz2597"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1159\/000518632"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602235103"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.078600"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.037"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(83)90084-8"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104292"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1825"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e02-09-0598"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821401116"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.07.006"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511397200"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1307-x"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.15.3896"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.117.018839"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.12.003"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00425-06"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.10.0533"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013010076"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0071519"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32634-0"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26346-0"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101582"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-021-00411-9"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/176207\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:48:51Z","timestamp":1779230931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/176207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":74,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,12,2]]},"published-print":{"date-parts":[[2025,2,3]]}},"alternative-id":["10.1172\/JCI176207"],"URL":"https:\/\/doi.org\/10.1172\/jci176207","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.03.560700","asserted-by":"object"}]},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,2]]},"article-number":"e176207"}}