Activation of Angiotensin-Converting Enzyme 2 Mitigates Gastrointestinal Acute Radiation Syndrome.

Abstract

In a radiation mass casualty event, exposed populations will suffer dose-dependent toxicity to multiple organ systems. Although several therapies are US Food and Drug Administration-approved for treatment of the hematopoietic acute radiation syndrome (ARS), there are no US Food and Drug Administration-approved medical countermeasures for either acute gastrointestinal (GI) injury or multiorgan delayed effects of acute radiation exposure (DEARE). Prior data suggest activation of the alternative renin angiotensin system (RAS) enzyme angiotensin-converting enzyme 2 (ACE2) has therapeutic potential for mitigating multiorgan radiation injury, including GI-ARS. Here, we evaluated whether activation of ACE2 mitigates GI-ARS in rodent models and protects against DEARE in GI-ARS survivors. GI recovery was assessed after treatment with ACE2 activator diminazene aceturate (DIZE) or an engineered form of the ACE2 protein with enhanced catalytic activity (ACE2 T371L/Y510Ile) in rodent partial body irradiation (PBI) models. Single-cell RNA sequencing was performed after irradiation and DIZE treatment to assess the cellular target of ACE2 activation. Mitigation of DEARE was assessed in a cohort of ARS survivors after DIZE treatment. Radiation induced a marked loss of GI ACE2 expression, most notably within mature enterocyte populations. ACE2 activation accelerated recovery of intestinal progenitor cells with high proliferative capacity and mucosal defense function. After 13.5 Gy PBI, DIZE improved survival in male rats during both ARS (days 0-30; P = .0008) and DEARE (days 30-200; P < .0001) compared with vehicle control. In female rats exposed to 13.5 Gy PBI, DIZE treatment improved all-cause morbidity through ARS and DEARE after 13.5 Gy PBI (P = .0025). Treatment with catalytically enhanced ACE2 variant T371L/Y510Ile accelerated recovery of ACE2 expression and improved survival during GI-ARS in male C57BL/6 mice exposed to 12.5 Gy PBI (P = .038). Activation of ACE2 promotes GI recovery during GI-ARS and mitigates lethal DEARE. Together, these data demonstrate alternative RAS enzyme ACE2 expression within the GI tract regulates radiation response and the alternative RAS axis is targetable for development of medical countermeasure.