ACE 2 deficiency increases NADPH ‐mediated oxidative stress in the kidney

Angiotensin‐converting enzyme 2 ( ACE 2) is highly expressed in the kidney and hydrolyzes angiotensin II (Ang II) to Ang(1–7). Since Ang II is a strong activator of oxidative stress, we reasoned that ACE 2 could be involved in the regulation of renal oxidative stress by governing the levels of Ang II. We, therefore, assessed levels of oxidative stress in kidney cortex of ACE 2 knockout and wild‐type littermate mice under baseline conditions. We found multiple markers of increased oxidative stress in ACE 2 KO mice. NADPH oxidase activity was increased in kidney cortex from ACE 2 KO mice as compared to WT (227 ± 24% vs.100 ± 19%, P  < 0.001). However, kidney catalase and superoxide dismutase activities were not different between groups. Exogenous Ang II was degraded less efficiently by kidneys from ACE 2 KO mice than WT mice, and administration of an AT 1R blocker (losartan 30 mg/kg/day) resulted in normalization of NADPH oxidase activity in the ACE 2 KO . These findings suggest that an AT 1R‐dependent mechanism contributes to increased ROS observed in the ACE 2 KO . This study demonstrates that genetic deficiency of ACE 2 activity in mice fosters oxidative stress in the kidney in the absence of overt hypertension and is associated with reduced kidney capacity to hydrolyze Ang II . ACE 2 KO mice serve as a novel in vivo model to examine the role of overactivity of NADPH oxidase in kidney function.