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No other physiological state is characterized by such high levels of renin, angiotensinogen, angiotensin II and aldosterone as occurs in pregnancy. Increased activity of the circulating renin-angiotensin-aldosterone system (cRAAS) and possibly the intrarenal renin-angiotensin system (RAS) counteract the effects of pregnancy on maternal cardiovascular and renal function caused by ovarian hormones. Of particular importance is the early activation of the cRAAS by estrogen-stimulated production of angiotensinogen, freeing it from feedback control of active renin release. This leads to increased salt and water retention that fills the maternal cardiovascular system, which is expanding under the influence of relaxin and other factors. The ovarian RAS plays key roles in ovulation and steroidogenesis. Placental and decidual RASs may play important roles in placentation and in regulating the timing of parturition. Thus, increased activity of tissue and circulating renin-angiotensin systems in pregnancy and their coordinated control are required to maintain pregnancy and ensure a healthy outcome.

During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Expression of the placental renin-angiotensin system (RAS) is highest in early pregnancy. While the RAS and oxygen both stimulate angiogenesis, how they interact within the placenta is unknown. We postulated that low oxygen increases expression of the proangiogenic RAS pathway and that this is associated with increased VEGF in a first trimester human trophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were cultured in one of three oxygen tensions (1%, 5% and 20%). RAS and VEGF mRNA expression were determined by qPCR. Prorenin, angiotensin converting enzyme (ACE) and VEGF protein levels in the supernatant, as well as prorenin and ACE in cell lysates, were measured using ELISAs. Low oxygen significantly increased the expression of both angiotensin II type 1 receptor (AGTR1) and VEGF (both P < 0.05). There was a positive correlation between AGTR1 and VEGF expression at low oxygen (r = 0.64, P < 0.005). Corresponding increases in VEGF protein were observed with low oxygen (P < 0.05). Despite no change in ACE1 mRNA expression, ACE levels in the supernatant increased with low oxygen (1% and 5%, P < 0.05). Expression of other RAS components did not change. Low oxygen increased AGTR1 and VEGF expression, as well as ACE and VEGF protein levels, suggesting that the proangiogenic RAS pathway is activated. This highlights a potential role for the placental RAS in mediating the proangiogenic effects of low oxygen in placental development.

This chapter details the development of the renal vasculature, the RAS, and the neural supply to the kidney. The sensitivity of the developing kidney to disruption of the activity of the fetal RAS is described. The fetal kidney has a high RVR and a low RBF and GFR. The effects on RBF and GFR of the RSNs, vasoactive peptides, and endothelium-derived factors such as NO are described. There are several unique features about the fetal renal vascular responses. First, it appears that endothelin can mediate a vasodilator response in the fetal circulation through stimulation of NO production. Second, stimulation of RSNs after adrenoreceptor blockade causes renal vasodilation.

The increased RBF that occurs in pregnancy is due to equivalent relaxation of afferent and efferent arterioles so that GPF is increased. Intracapillary glomerular hydrostatic pressure (Pgc) and the ultrafiltration coefficient (Kf) are unchanged. The increase in GPF is responsible for the increase in GFR. The mechanisms responsible for these changes in glomerular hemodynamics are unknown. To some extent they occur in the pseudopregnant rat; therefore, in that species it is likely that these changes in RBF and GFR are independent of the presence of the conceptus. A number of possible endocrine/paracrine factors may be responsible. NO is a likely candidate. Blockade of NO production normalizes RBF and GFR to nonpregnant levels and produces changes in glomerular structure similar to those seen in preeclampsia.

Publisher Summary In an adult the renin-angiotensin-aldosterone system (RAAS) is important in the control of sodium balance. Renin release is influenced by tubular sodium transport and the activity of the RAAS modifies renal sodium excretion. The end-result of this interaction between the RAAS and sodium balance is an inverse relationship between plasma renin activity and urinary sodium excretion. This chapter presents acute experiments, which were carried out on the fetal lamb in utero to examine the renal mechanisms that affect sodium excretion. It also explains that the sheep placenta is relatively impermeable to sodium, in which case the fetal kidney contributes to the control of sodium balance. Glomerulotubular balance minimizes the loss of sodium and potassium into urine resulting from fluctuations in glomerular filtration rate (GFR). Glomerulotubular balance is of greater functional significance in the fetus because GFR is variable and is directly related to arterial pressure. This dependency of GFR on arterial pressure indicates that there is no autoregulation of fetal GFR, just as there is no autoregulation of neonatal GFR.