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The present study was designed to determine ANG peptide content [ANG I, ANG II, ANG-(1-7)], ACE2 mRNA, and the immunocytochemical distribution of ANG-(1-7) and ACE2 in the uteroembryonic unit during early and late gestation in Sprague-Dawley rats and in a rat model of pregnancy-induced hypertension, the reduced uterine perfusion pressure (RUPP) model. At early pregnancy ANG-(1-7) and ACE2 staining were localized in the primary and secondary decidual zone and luminal and glandular epithelial cells. During late gestation, ANG-(1-7) and ACE2 staining was visualized in the labyrinth placenta and amniotic and yolk sac epithelium. Uterine ANG II concentration at early pregnancy was significantly decreased by 21-55% in the implantation and interimplantation sites compared with virgin rats, whereas ANG-(1-7) levels were maintained at prepregnancy levels. At late gestation, uterine concentrations of ANG I and ANG II were significantly increased (30% and 25%, respectively). In RUPP animals, ANG-(1-7) concentration is significantly reduced in the uterus (181 +/- 16 vs. 372 +/- 74 fmol/g of tissue) and placenta (143 +/- 26 vs. 197 +/- 20 fmol/g of tissue). ACE2 mRNA increased in the uterus of early pregnant compared with virgin rats, yet within the implantation site it was downregulated. At late pregnancy, ACE2 mRNA is elevated by 58% in the uterus and decreased by 59% in RUPP animals. The regulation of ANG-(1-7) and ACE2 in early and late pregnancy supports the hypothesis that ANG-(1-7) and ACE2 may act as a local autocrine/paracrine regulator throughout pregnancy, participating in the early (angiogenesis, apoptosis, and growth) and late (uteroplacental blood flow) events of pregnancy.

Abstract-Previously we demonstrated that kidney concentration and urinary excretion of angiotensin-(1-7) are increased during normal pregnancy in rats. Since this finding may reflect local kidney production of angiotensin-(1-7), we determined the immunocytochemical distribution of angiotensin-(1-7) and its newly described processing enzyme, ACE2, in kidneys of virgin and 19-day-pregnant Sprague-Dawley rats. Sprague-Dawley rats were killed at the 19th day of pregnancy, and tissues were prepared for immunocytochemical by using a polyclonal antibody to angiotensin-(1-7) or a monoclonal antibody to ACE2. Angiotensin-(1-7) immunostaining was predominantly localized to the renal tubules traversing both the inner cortex and outer medulla. ACE2 immunostaining was localized throughout the cortex and outer medulla and was visualized in the renal tubules of both virgin and pregnant rats. The quantification of angiotensin-(1-7) and ACE2 immunocytochemical staining showed that in pregnant animals, the intensity of the staining increased by 56% and 117%, respectively (PϽ0.05). This first demonstration of the immunocytochemical distribution of angiotensin-(1-7) and ACE2 in kidneys of pregnant rats shows that pregnancy increases angiotensin-(1-7) immunocytochemical expression in association with increased ACE2 intensity of staining. The findings suggest that ACE2 may contribute to the local production and overexpression of angiotensin-(1-7) in the kidney during pregnancy. Key Words: angiotensin Ⅲ renin-angiotensin system Ⅲ pregnancy Ⅲ kidney Ⅲ angiotensin-converting enzyme 2 P reviously we demonstrated for the first time that activation of the renin-angiotensin system (RAS) during pregnancy is associated with augmented kidney concentration and urinary excretion of angiotensin-(1-7) [Ang-(1-7)]. 1 Ang-(1-7), formed from either Ang I or Ang II and shown to exert vasodilatory, antiproliferative and natriuretic effects, 1-9 was the predominate angiotensin peptide found in the kidney and urine of pregnant rats, reaching levels that were 3-and 2.5-fold greater than Ang II in the kidney and urine, respectively. There was an increase in the Ang-(1-7)/Ang II, indicating that there may be increased enzymatic conversion of Ang II into Ang-(1-7). At the same time, there was no change in Ang-(1-7) in the circulation. These findings suggest that there may be an enhanced renal local production and overexpression of Ang-(1-7) in pregnancy without a systemic contribution.The profile of peptides in the kidney with increased content of Ang-(1-7) without a buildup in the levels of Ang II is consistent with an enzymatic pathway of a recently described enzyme of the RAS, ACE2. ACE2 is a carboxypeptidase that converts Ang I into Ang-(1-9), but it also exhibits high catalytic efficiency to generate Ang-(1-7) from Ang II. 10 -12 The ACE2 catalytic activity for Ang II as compared with Ang I is 400-fold higher, making Ang II a central player in the metabolic pathway for the formation of Ang-(1-7). Chappell et al 13 provided the first direct evidence f...