Analysis of Changes in the Renin-Angiotensin System during Pregnancy

Skinner, Sandford L.; Lumbers, Eugenie R.; Symonds, E. M.

doi:10.1042/cs0420479

Cited by 161 publications

(97 citation statements)

References 13 publications

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“…The mean K^ value of 5 7 jLiM contrasts with such values as 018.5 /iM (Haas and Coldblatt, 1967), 0-07/iM (Poulsen, 1968), 0155/iM (Roseuthal et al, 1971), 0-931 fxW (Could and Creen, 1971), 1-1 /xM (Krakoff, 1973) and 0-4 fxM (Favre and Vallotton, 1973) obtained in studies iu whicli concentration and specific activity of substrate were lower than in the present work. High values are, however, apparent in the publications of Helmer and Judson (1967), Skinner et al (1969Skinner et al ( , 1972 and Waldhansl and Lewandowski (1973). Skeggs et al (1968) described K,,, values between 3 6 and 50 /xM for a series of short linear synthetic peptide substrates reacting with humau renin but their findings do not assist in understanding the basis for the low affinity between the human reactants, because, for native substrates, affinity is likely to depend to some extent upon protein structure at a distance from the hydrolytic site.…”

Section: Discussionmentioning

confidence: 97%

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Purification, Properties and Kinetics of Sheep and Human Renin Substrates

Skinner

Dunn

Mazzetti

et al. 1975

Aust J Exp Biol Med

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Summary. Sheep plasTiia renin substralf was purified 1,200-fold l>y usinjj nephrfctomised sheep plasma, followed by DEAE-Sephadex chromatojijraphy and gel filtration. Th? purified substrate contained 8 nji angiotensin Il/nig protein and had an estimated molecular vveijjht of 52,000. The kinetic characteristics of the purified substrate were identical both to those of tuipurified nephrectomised sheep plasma and to normal sheep plasma substrates. At pH 7-5, K,,, of the human renin-sheep substrate reaction was 0-29 [iM and for sheep reninsheep substrate. 2-0 fiM. Sheep substrate was .susceptible to peptic diHeslion with generation of pepsitenshi.Hunuin renin substrate was less readily purified. DEAE-Sephadex chromatography of plasma from pregnant women at 36-40 weeks' gestation produced a 70-fold increase in purity (0-9 ng angiotensin Il/mg protein). No further increase was achieved with gel filtration. Human renin substrate behaved as a larger (mol. wt. 82.000) more anionic protein than sheep substrate and was resistant to the proteolytit actions of both pepsin and shi-ep renin. K,,, for the human renin-human substrate reaction was high and conid not be accurately detennined (range 3-8 nM. mean 5-7 ^iM). The presence of human substrate in a human rcnin-sheep substrate system did not alter the measured initial velocity.In both shet'p and man, the nonnal concentration (»f ri^nin substrate is considerably less than K,,, and must therefore be considered a dtterminant of angiotensin production rate j>i vivo.

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Section: Discussionmentioning

confidence: 97%

“…The latter source was exploited for its high concentration of renin substrate (Skinner et al 1972). Heparin (10 units/ml) was added to all blood, the plasma removed, pooled into separate noimal or pregnancy stocks and stored at -IS".…”

Section: Methodsmentioning

confidence: 99%

Purification, Properties and Kinetics of Sheep and Human Renin Substrates

Skinner

Dunn

Mazzetti

et al. 1975

Aust J Exp Biol Med

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“…In normal human pregnancy, Ang II is increased in the maternal circulation (41,55). As we have shown here, one of the local functions of the increased Ang II in the placenta may be to induce local PAI-1 production.…”

Section: Discussionmentioning

confidence: 99%

“…Realizing that the maternal fetal interface has a locally active renin-angiotensin system (32,41) and that PAI-1 gene expression is regulated by Ang II in other systems (25,28,29) we conducted experiments to determine if the abundance of PAI-1 mRNA is induced by Ang II in human trophoblasts. For these studies we used HTR-8/Svneo cells, an immortalized line of human trophoblasts.…”

Section: Pai-1 Mrna Abundance Is Increased By Ang II In Humanmentioning

confidence: 99%

Angiotensin II Inhibits Human Trophoblast Invasion through AT1 Receptor Activation

Xia

Wen

Kellems

2002

Journal of Biological Chemistry

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Trophoblast implantation depends, in part, on the controlled production of plasmin from plasminogen, a process regulated by plasminogen activators and plasminogen activator inhibitors. We have determined that angiotensin II (Ang II) stimulates plasminogen activator inhibitor-1 (PAI-1) synthesis and secretion in human trophoblasts in a time-and concentration-dependent manner. Our results indicate that Ang II activates PAI-1 gene expression through the AT1 receptor and involves the calcium-dependent activation of calcineurin and the nuclear translocation of NFAT. Increased PAI-1 synthesis and secretion is associated with reduced trophoblast invasion as judged by an in vitro invasion assay. These studies are the first to link the renin-angiotensin system with the fibrinolytic system to regulate trophoblast invasion.The fibrinolytic system is best known for its role in the regulated digestion of fibrin clots. A key component of this system is plasminogen, an inactive zymogen, which is converted into the active protease, plasmin, by the action of a plasminogen activator termed tissue-type plasminogen activator (tPA).1 The ability of tPA to activate plasminogen is substantially enhanced by its association with the substrate, fibrin (1). Plasminogen can also be activated (i.e. converted to plasmin) by the action of another plasminogen activator, urokinase-type plasminogen activator (uPA) (2-6). In contrast to tPA, uPA is not associated with fibrin clots but instead is often associated with a specific cell surface receptor (uPAR) (7), which is thought to play a key role in cell migration and invasion (8). In this role, uPA is synthesized as an inactive single-chain proenzyme that can be stored or secreted. Secreted uPA is cleaved into the active two-chain molecule upon binding to uPAR on the surface of cells. Following activation, receptorbound uPA is capable of converting plasminogen into plasmin, the latter of which is able to degrade several key components of the extracellular matrix (ECM) (9). It is widely accepted that uPA initiates a cascade of proteolysis at the cell surface, which in turn leads to the degradation of the ECM, thereby promoting cellular migration. It is now clear that the uPA-regulated aspect of the fibrinolytic system plays a key role in mediating ECM degradation and cell invasion. Plasminogen activator activity is controlled by plasminogen activator inhibitors (PAIs) of which PAI-1 is the predominant physiological inhibitor (1, 10, 11). PAI-1 is an ECM glycoprotein that is capable of inhibiting both free and receptor-bound uPA through the formation of an irreversible covalent complex (12). In this way PAI-1 is believed to control cell migration and invasion in tumor growth and angiogenesis (13-16).Numerous studies suggest that PAI-1 production by human trophoblasts plays an important role in trophoblast invasion and placental development (17, 18). The human hemochorial placenta is a highly invasive structure in which a subpopulation of placental trophoblast cells invades the uterus, its underlyi...

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“…Thus, in his studies with Malcolm Symonds and Eugenie Lumbers of renin levels during pregnancy, Sandy was able to demonstrate a dissociation between PRA and PRC, leading to the proposal that the PRC method measures both active and inactive renin and that early pregnancy is associated with increased amounts of inactive renin in plasma. 8 Sandy subsequently modified his methods to measure the separate concentrations (with sheep angiotensinogen) of active and total (acid-or trypsin-activated) renin, the difference between active and total renin representing inactive renin (prorenin). In 1968 Sandy was appointed Reader in Physiology at The University of Melbourne, where he remained for the remainder of his career.…”

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confidence: 99%