Enhancement of the classical renin-angiotensin system (RAS), known as the angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damage including cognitive decline. On the other hand, the ACE2/Ang-(1-7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the ACE/Ang II/AT1 receptor axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1-7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function.Design and method:
Male 10-week-old C57BL6 (wild-type; WT) and ACE2 knockout (KO) mice were subjected to the Morris water maze task to evaluate spatial cognitive function. After the Morris water maze task, cerebral blood flow (CBF) was analyzed by laser speckle flowmetry. Oxidative stress in the hippocampus was evaluated. Expression of brain-derived neurotrophic factor (BDNF) was measured by real-time RT-PCR and Western blot.Results:
There were no significant differences in body weight, brain weight and systolic blood pressure between ACE2KO and WT mice. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice, with no significant difference in CBF. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex, with no significant difference between ACE2KO and WT mice. AT1 receptor mRNA in the hippocampus was higher in ACE2KO mice compared with WT mice, whereas AT2 receptor mRNA in the hippocampus did not differ between the two strains. Superoxide anion production increased in ACE2KO mice, with increased NADPH oxidase subunits mRNAs in the hippocampus. Protein level of SOD3 decreased in ACE2KO mice compared with WT mice. BDNF mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Administration of Ang-(1-7) (0.5 mg/kg/day) attenuated the cognitive decline in ACE2KO mice without changes in systolic blood pressure.Conclusions:
Taken together, ACE2 deficiency resulted in impaired cognitive function at least in part due to enhanced oxidative stress and a decrease in BDNF.