Abstract
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 damages including cognitive decline. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS 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. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22phox, p40phox, p67phox, and gp91phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF.
Highlights
The renin–angiotensin system (RAS) has important roles in blood pressure regulation and cardiovascular function
The Ang-(1–7)/ACE2/Mas receptor axis has been highlighted as the counterpart of the Ang II/Ang-converting enzyme (ACE)/Ang II type 1 (AT1) receptor axis, and Ang-(1–7) in the brain is known to exert effects related to blood pressure regulation as the depressor arm, and to act as a cerebroprotective component of RAS by reducing cerebral infarct size and neuronal apoptosis
ACE2 is widely expressed in brain areas involved in both the central regulation of blood pressure and cardiovascular function and disease, and the ACE2 level appears to be strongly regulated by other components of RAS.11
Summary
The renin–angiotensin system (RAS) has important roles in blood pressure regulation and cardiovascular function. Chiu et al. reported that ARBs may be associated with a reduced risk of dementia in high-vascular-risk individuals, and that patients exposed to ARBs at higher cumulative doses experienced greater protection from dementia and its subtypes, based on a population-based cohort study of 24,531 matched pairs with data from the Taiwan National Health Insurance Research Database. These clinical results support the idea that both AT1 receptor blockade and Ang II type 2 (AT2) receptor stimulation by unbound Ang II are important in the neuroprotective effect of ARBs.. A new axis of RAS, the ACE2/Ang-(1–7)/Mas axis has been highlighted as the counteracting partner of the ACE/Ang II/AT1 receptor. Ang-(1–7) is produced from Ang I or Ang II by the catalytic activity of ACE2, and the discovery that Ang-(1–7) opposes the pressor, proliferative, fibrotic, and thrombotic actions mediated by Ang II via the AT1 receptor has contributed to the realization that RAS is composed of two opposing arms.
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