The Renin-angiotensin system and its autocrine, papacrine and endocrine aspects in human pregnancy : characteristics and function of the placenta system
(1996)
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- Authors
- Supervisors
- De Hertogh, René
- Abstract
- The existence of the renin-angiotensin system in mammals was clearly established by simultaneous studies from Braun-Ménendèz et al (1940) and Page (1940), four decades after the discovery of renin (Tigerstedt and Bergmann, 1898). From this period until the late 1960’s, the only known sources of the primary components of the system were the kidney producing rennin, the liver expressing angiotensinogen and the lung where angiotensin converting enzyme is synthesized. It was then reported that after its secretion into the blood circulation, renin cleaved the alpha-2-globulin angiotensinogen to form the decapeptide angiotensin I and that this product was rapidly converted into the octapeptide angiotensin II by the action of angiotensin converting enzyme (Ganten et al. 1973; Peach, 1977; Mathias et al. 1984). <BR> Traditionally, the renin-angiotensin system was considered as a purely endocrine system, and angiotensin II, the main peptide effector of the system, was supposed to act mainly outside of its site of production. Moreover, the only known physiological effects of the circulating rennin-angiotensin system were associated with the regulation of the arterial blood pressure and sodium and water homeostasis (Goldblatt, 1984; Peach, 1977; Mathias et al. 1984). <BR> In recent years, a number of investigations have demonstrated the existence of lacol renin-angiotensin systems in various tissues. Indeed, several organs such as brain, heart, lung, liver, adrenal gland, kidney, uterus, ovary, placenta and fetal membranes synthesize renin, angiotensin converting enzyme and/or angiotensinogen. These organs also express angiotensin II receptors, thus suggesting the presence of a locally functional renin-angiotensin system (Whitebread et al. 1989; de Gasparo et al. 1992; Kalenga et la 1996a). A few tissues express the genes for certain components of the system only in pathological conditions. For instance, in the pancreas, the renin gene is expressed only in tumoral cells (Ruddy et al 1982; Atlas et al 1984; Penchet et al 1986). <BR> Angiotensin II acts through two main receptor subtypes, termed AT1 and AT2. these have been characterized by means of selective ligands such as Dup 753 (losartan) which preferentially binds to the AT1 subtype (Kd ± 30 ,M for AT1 vs ± 30 µM for AT2) and CGP 42112A which is specific for the AT2 subtype (Kd ± 0.5 nM for AT2 vs ± 3µM for AT1). Disulfide reducing agents like dithiothreitol also allow to distinguish the two receptors : they increase the binding to the AT2 receptor but decrease the density of the AT1 subtype (Whitebread et al. 1989; Rogg et al. 1990; Bumpus et al. 1991; Feuillan et al. 1993). <BR> The local and circulating renin-angiotensin systems are not competing entities but could interact at several levels to regulate local and systemic blood circulations and probably other tissue functions. One may thus consider that angiotensin II acts not only as an endocrine but also as a paracrine or an autocrine factor. It has event been postulated that angiotensin II may also act as an intracrine factor by modulating some intracellular events (Paul et al. 1992). <BR> Pregnancy is accompanied by an important activation of the circulating renin-angiotensin system. Plasma renin, angiotensinogen and angiotensin II are markedly elevated in pregnant women, compared to nonpregnant subjects (Weir et al. 1975; Baker et al. 1990; Hsueh et al. 1982; Kalenga, 1992a; Kalenga et al. 1996a). However, a number of questions remain unanswered about the origin, the regulation and the physiological significance of the renin-angiotensin system components found in high concentrations during pregnancy. <BR> The placenta could be one of the main sites contributing to the activation of the maternal plasma renin-angiotensin system since it synthesizes all essential components of the system. Locally, the placental system could play a central role in the regulation of blood flow in the uterofetoplacental complex and the transfer of oxygen and nutrients to the fetus. In addition, it could interact with a number of placental hormones like estrogens, human placental lactogen (hPL) and pregnancy-specific β1-glycoprotein (SP1), thus contributing to fetal development (Kalenga, 1992a ; Kalenga et al., 1996a). <BR> the purpose of this thesis is to define, in nonpregnant and pregnant women, the main sites of production of the renin-angiotensin system components and to clarify how local renin-angiotensin systems function and interact with the circulating system. During pregnancy, the placental system is extensively examined to precise its activity and functions and to determine whether it substantially contributes to the activation of the maternal and fetal circulating renin-angiotensin systems. Clinically, an important question is to know whether the maternal, fetal and chorioplacental renin-angiotensin systems are affected in preeclamptic pregnancies. <BR> This monography is subdivided in three parts. The first part is a general review on the biochemistry and the physiology of the renin-angiotensin system and the second defines the particularities of various local systems and the profile of the circulating system during the menstrual cycle. In the third part, we discuss, based in the literature and our personal observations, the profile of the maternal and fetal plasma renin-angiotensin systems and more extensively the characteristics and function of the placental renin-angiotensin system in normal and hypertensive human pregnancy
- Affiliations
Citations
Kalenga, M. K. (1996). The Renin-angiotensin system and its autocrine, papacrine and endocrine aspects in human pregnancy : characteristics and function of the placenta system. https://hdl.handle.net/2078.5/111361