New insights into the importance of aminopeptidase A in hypertension

Abstract

The renin-angiotensin system (RAS) plays an important role in the maintenance of normal blood pressure and the etiology of hypertension; however, minimal attention has been paid to the degradation of the effector peptide, angiotensin II (AngII). Since aminopeptidase A (APA)-deficient mice develop hypertension APA appears to be an essential enzyme in the control of blood pressure via degradation of AngII. The robust hypertension seen in the spontaneously hypertensive rat (SHR) is due to activation of the RAS, and an accompanying decrease in kidney APA. Changes in APA have also been measured during the activation of the RAS in the Goldblatt hypertension model and Dahl salt-sensitive (DSS) rat. The DSS rat shows an elevation in renal APA activity at the onset of hypertension suggesting a protective role against elevations in circulating AngII, followed by decreased APA activity with advancing hypertension. Changes seen in human maternal serum APA activity during preeclampsia are similar to changes measured in renal APA in the DSS rat model. APA activity is higher than during normal pregnancy at the onset of preeclampsia, and with advancing preeclampsia (severe preeclampsia) declines below that seen during normal pregnancy. Serum APA activity is also increased during hormone replacement therapy (HRT), perhaps in reaction to elevated levels of AngII. Thus, it appears important to consider the relationship among activation of the RAS, circulating levels of AngII, and the availability of APA in hypertensive disorders.

Fig. 1

The renin-angiotensin cascade. Angiotensinogen is cleaved by renin to form angiotensin I. Angiotensin I is converted to AngII by angiotensin-converting enzyme. The N-terminal aspartic acid is cleaved from AngII to form AngIII, and the N-terminal arginine is cleaved from AngIII to form AngIV

Fig. 2

Representative example of the effects of partially purified APA from human placenta on blood pressure in an SHR when intravenously infused over a 1 min duration. Mean arterial base level blood pressure was approximately 165 mmHg with a maximum decrease to approximately 80 mmHg 4 min following treatment

Fig. 3

Analysis of the effects of APA deficiency on blood pressure levels. (A) Systolic and (B) mean arterial blood pressure of APA−/−, APA+/− and APA+/+ mice at 3 months of age were determined by tail-cuff measurement. The mean ± SEM for each group is represented by an open circle and a bar. Each group consisted of 9–15 animals. *P < 0.05

Fig. 4

Effects of chronic AngII infusion on systolic blood pressure. (A) Daily changes in systolic blood pressure accompanying an AngII infusion in /APA−/−(○) or /APA+/+(•) mice. The osmotic pumps were implanted on day 0. (B) Increases in systolic blood pressure from base level on day 0 to the levels on day 2 in APA−/− and APA+/+ mice. Values are mean ± SEM. *P < 0.05

Fig. 5

Age-related changes in renal APA activity in DSR rats. DSR rats were fed an 8%-salt diet (closed squares) or a 0.3%-salt diet (open squares). Values are mean ± SD (n = 6 at each point). *P < 0.05

Fig. 6

Age-related changes in renal APA activity in DSS rats. DSS rats were fed an 8%-salt diet (closed circles) or a 0.3%-salt diet (open circles). Values are mean ± SD (n = 6 at each point). *P < 0.05

Fig. 7

Changes in maternal systolic blood pressure in response to infusion of AngII in (A) WKY rats, and (B) SHRs. AngII (200 ng/kg per min) was infused from day 15 of gestation in pregnant animals (solid lines) and in non-pregnant animals (dotted lines) at the same weeks (arrows). AngII increased systolic blood pressure more rapidly and markedly in non-pregnant than in pregnant WKY rats. Pregnant SHRs showed a loss of refractoriness to the hypertensive effect of exogenously infused AngII (n = 10 animals per group) *P < 0.05