Sex Differences in Angiotensin-Converting Enzyme Modulation of Ang (1-7) Levels in Normotensive WKY Rats

BACKGROUND Levels of the vasodilatory peptide angiotensin (Ang) (1-7) have been reported to be greater in females than in males, although the molecular mechanism responsible for this is unknown. Angiotensin-converting enzyme (ACE), ACE2, and neprilysin are key enzymes regulating Ang (1-7) formation. We conducted a study to determine the effect of sex on the activities of ACE, ACE2, and neprilysin in the kidneys of normotensive rats. We hypothesized that greater ACE2 or neprilysin activity in females would result in enhanced Ang (1-7) formation as compared with that in males. METHODS We measured the enzymatic activities of ACE, ACE2, and neprilysin in the renal cortex and medulla of 12-week-old male and female WKY rats. We treated additional rats with vehicle or enalapril (10 mg/kg/day in drinking water) for 14 days, and measured their Ang II and Ang (1-7) levels. RESULTS Renal cortical activity of ACE was greater in female than in male WKY rats (P < 0.05), but the activity of ACE in the renal medulla was not significantly different in the two sexes. Renal cortical and medullary ACE2 and neprilysin activities were comparable in male and female WKY rats. Treatment with enalapril significantly decreased Ang II levels in the renal cortex and medulla of male and female WKY rats as compared with those in vehicle-treated controls (P < 0.05); enalapril did not change the plasma levels of Ang II. Cortical levels of Ang (1-7) were higher in vehicle-treated females than in vehicle-treated males (P < 0.05), and treatment with enalapril decreased Ang (1-7) levels only in females (P < 0.05). CONCLUSIONS Our data supports a role for ACE in the formation of renal cortical Ang (1-7) in female WKY rats that is absent in males.