Regulation of Brain Neprilysin and ACE2 in Transgenic Rats During Aging

Angiotensinogen (Aogen), the precursor to angiotensin (Ang) II and Ang-(1-7) is expressed in astrocytes and neurons. Neprilysin and angiotensin-converting enzyme 2 (ACE2) are potential enzymes for Ang-(1-7) formation from Ang I and Ang II respectively. We assessed their regulation in brain during aging in transgenic rats (ASrAogen) with an Aogen antisense behind a glial-promoter. These exhibit a 90% reduction in brain Aogen levels and low blood pressure that is maintained during aging at 16 and 70 weeks in hypothalamus (HYPO) and medulla (MED). HYPO ACE2 mRNA was 45% higher in ASrAogen than control SD rats and higher in older ASrAogen vs. younger rats. Neprilysin mRNA tended to increase during aging and values were 80% higher in ASrAogen vs. SD. In MED, mRNA of both enzymes during aging tended to decrease with no difference between strains. Immunocytochemistry revealed ACE2-staining in both strains localized to circumventricular organs and plexus choroideus. Thus, the ACE2 distribution suggests the enzyme contributes to Ang-(1-7) in cerebrospinal fluid but not neural pathways. Up regulation of mRNA for both enzymes in HYPO of ASrAogen rats may represent compensation for loss of glial-derived peptides. Lack of differences in MED between strains may reflect distinct sources (neural vs. glial) of peptides responsible for enzyme regulation in the two brain areas.