Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs.

Abstract

We previously reported that excessive angiotensin-II (AT)->AT receptor-1 (ATR1) signaling results in sickle cell anemia (SCA)-associated nephropathy. Herein, we showed hyperangiotensinemia in SCA results from high erythroid cell-generated reactive oxygen species (ROS), which oxidized angiotensinogen (ATGN) and favored its rapid conversion to AT. Increased AT->ATR1 signaling in SCA erythroid cells generated ROS and created a positive feedback loop of ROS->oxidized ATGN->AT->ATR1-> ROS, perpetuating the hyperangiotensinemia. ATR1-blocker, losartan, reduced erythrocyte ROS, oxidized-AGTN, and AT levels. The ROS->AT->ATR1->ROS 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->ATR1 signaling, which acted in harmony with increased erythropoietin signaling. Further, instead of the canonical AT->ATR1-> NADPH-oxidase->ROS signaling in steady-state erythropoiesis, AT->ATR1 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 demonstrated that AT->ATR1 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.