{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T20:07:40Z","timestamp":1778789260374,"version":"3.51.4"},"reference-count":50,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":57,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"crossref","award":["U01HL117709"],"award-info":[{"award-number":["U01HL117709"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100017540","name":"NHLBI Division of Intramural Research","doi-asserted-by":"crossref","award":["R34 HL108752"],"award-info":[{"award-number":["R34 HL108752"]}],"id":[{"id":"10.13039\/100017540","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,8]]},"abstract":"<jats:p>We previously reported that excessive angiotensin-II\u2192AT receptor-1 (AT\u2192ATR1) signaling results in sickle cell anemia\u2013associated (SCA-associated) nephropathy. Herein, we showed that hyperangiotensinemia in SCA results from high erythroid cell\u2013generated reactive oxygen species (ROS), which oxidized angiotensinogen (ATGN) and favored its rapid conversion to AT. Increased AT\u2192ATR1 signaling in SCA erythroid cells generated ROS and created a positive feedback loop of ROS\u2192oxidized ATGN\u2192AT\u2192ATR1\u2192ROS, perpetuating the hyperangiotensinemia. ATR1 blocker, losartan, reduced erythrocyte ROS, oxidized ATGN, and AT levels. The ROS\u2192AT\u2192ATR1\u2192ROS loop was driven by sickle erythropoiesis, as it was reproduced when WT mice were transplanted with SCA hematopoiesis. Using SCA and WT mice with germline- and erythroid-specific ATR1 deficiency, we found that stress erythropoiesis, but not steady-state erythropoiesis, was critically dependent on erythroid AT\u2192ATR1 signaling, which acted in harmony with increased erythropoietin signaling. Furthermore, instead of the canonical AT\u2192ATR1\u2192NADPH-oxidase\u2192ROS signaling in steady-state erythropoiesis, AT\u2192ATR1 signaling in stress erythroid cells increased mitochondrial mass and dysfunctional mitochondria, which thereby increased ROS. SCA mice with erythroid-specific ATR1 deficiency had decreased RBC accumulation of dysfunctional mitochondria and decreased ROS, which reduced SCA-associated nephropathy. Overall, we demonstrate that AT\u2192ATR1 signaling was essential for stress erythropoiesis but led to increased dysfunctional mitochondria retention in mature RBCs, which generated ROS and perpetuated hyperangiotensinemia, resulting in end-organ damage.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>&lt;strong&gt;We explore the role of angiotensin signaling in stress erythropoiesis, where it sustains erythroid expansion but also promotes retention of dysfunctional mitochondria in erythroid cells&lt;\/strong&gt;<\/jats:p>","DOI":"10.1172\/jci.insight.200722","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T14:10:22Z","timestamp":1774015822000},"source":"Crossref","is-referenced-by-count":0,"title":["Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs"],"prefix":"10.1172","volume":"11","author":[{"given":"Parul","family":"Rai","sequence":"first","affiliation":[{"name":"Division of Hematology,"},{"name":"Cancer and Blood Diseases Institute,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swarnava","family":"Roy","sequence":"additional","affiliation":[{"name":"Cancer and Blood Diseases Institute,"},{"name":"Division of Experimental Hematology and Cancer Biology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paritha","family":"Arumugam","sequence":"additional","affiliation":[{"name":"Cancer and Blood Diseases Institute,"},{"name":"Division of Experimental Hematology and Cancer Biology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diamantis G.","family":"Konstantinidis","sequence":"additional","affiliation":[{"name":"Cancer and Blood Diseases Institute,"},{"name":"Division of Experimental Hematology and Cancer Biology, 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