Age-related alterations in the brain ACE2/Ang-(1-7)/Mas receptor axis in normotensive and spontaneously hypertensive rats

Aging has been associated with hypertension, end-organ damage, and cognitive dysfunction. The protective axis of the renin-angiotensin system, consisting of angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor (MasR), exerts anti-hypertensive and cerebroprotective effects. Thus, we aimed to evaluate whether aging and hypertension may be associated with region-specific changes in the ACE2/Ang-(1-7)/MasR axis in the brainstem (BS), hypothalamus (Hypot), hippocampus (Hippo), and cerebral cortex (CC) of Wistar rats and spontaneously hypertensive rats (SHRs) at different ages. Ang-(1-7) levels were measured by radioimmunoassay, and ACE2 and MasR expression by immunoblotting. In Wistar rats, Ang-(1-7) levels decreased with age in all brain areas. At a prehypertensive stage (1 month of age), SHRs exhibited lower Ang-(1-7) levels than Wistar rats in BS, Hypot, Hippo, and CC. In SHRs, Ang-(1-7) levels increased at 3 months and subsequently decreased at 12 months in the BS, Hypot, and Hippo, whereas cortical levels declined with age. No differences in Ang-(1-7) levels between both strains were found at 3 and 12 months of age. In line with the reduced hypothalamic Ang-(1-7) levels, MasR and ACE2 protein abundance were also decreased in the Hypot of 1-month-old SHRs compared with age-matched Wistar rats. In contrast, MasR expression was higher in BS of 1-month-old SHRs compared with age-matched Wistar rats, suggesting a compensatory response. At 1 month of age, ACE2 and MasR protein levels did not differ between strains in the Hippo or CC. We conclude that abnormal changes in the expression of the brain ACE2/Ang-(1-7)/MasR axis early in life may predispose to the development of hypertension with age.