Abstract
We previously reported that excessive angiotensin-II→AT receptor-1 (AT→ATR1) signaling results in sickle cell anemia–associated (SCA-associated) nephropathy. Herein, we showed that 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 ATGN, 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. Furthermore, 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 demonstrate 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.
Authors
Parul Rai, Swarnava Roy, Paritha Arumugam, Diamantis G. Konstantinidis, Sithara Raju Ponny, Marthe-Sandrine Eiymo Mwa Mpollo, Archana Shrestha, Theodosia A. Kalfa, Punam Malik
Figure 4
Angiotensin signaling in stress erythropoiesis promotes the accumulation of dysfunctional mitochondria, which generate high levels of reactive oxygen species (ROS) in erythrocytes.
