Fetal hormonal, renal, and behavioral regulation

446

Braz J Med Biol Res 41(6) 2008

J. Guan et al.

www.bjournal.com.br

 

Fetal development of regulatory

mechanisms for body fluid homeostasis

 

J. Guan1,2*, C. Mao1*, X. Feng1, H. Zhang1, F. Xu1, C. Geng1, L. Zhu1 , A. Wang1 and

Z. Xu1,3

1.Perinatal Biology Center, Soochow University School of Medicine, Suzhou, China

2.Department of Microbiology, Bengbu Medical College, Bengbu, Anhui, China

3.Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, USA

 

 

Correspondence to: Z. Xu, Perinatal Research Laboratory, Soochow University School of Medicine,

Suzhou, China or Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda,

CA 92350, USA

E-mail: zxu@llu.edu

 

The balance of body fluids is critical to health and the development of diseases. Although quite a few review papers have shown that several mechanisms, including hormonal and behavioral regulation, play an important role in body fluid homeostasis in adults, there is limited information on the development of regulatory mechanisms for fetal body fluid balance. Hormonal, renal, and behavioral control of body fluids function to some extent in utero. Hormonal mechanisms including the
renin-angiotensin system, aldosterone, and vasopressin are involved in modifying fetal renal excretion, reabsorption of sodium and water, and regulation of vascular volume. In utero behavioral changes, such as fetal swallowing, have been suggested to be early functional development in response to dipsogens. Since diseases, such as hypertension, can be traced to fetal origin, it is important to understand the development of fetal regulatory mechanisms for body fluid homeostasis in this early stage of life. This review focuses on fetal hormonal, behavioral, and renal development related to regulation of body fluids in utero.
 

Key words: Fetal body fluids; Fetal hormonal regulation; Fetal renal regulation; Swallowing
 

Research partially supported by the National Natural Science Foundation (#30570915), Jiangsu Natural Science Key Grant (BK2006703), Suzhou Key Lab Grant (SZS0602), Suzhou International Scientific Cooperation Grant (SWH0716), and Suda Medical Development Key Grant for C. Mao.
 

*These authors contributed equally to this study.
 

Received January 10, 2008. Accepted 14 April,
2008

 

Brazilian Journal of Medical and Biological Research (2008) 41: 446-454

ISSN 0100

 

 

 

 

Introduction

Water and sodium are the two major
determinants of  body fluid homeostasis.
Water accounts for approximately 60% of
body weight, with two-thirds of body water
within cells and one-third in interstitial spaces
and plasma. Addition (through ingestion) or
loss (through excretion, salivary loss,
respiration, perspiration, etc.) of either water
or sodium to/from the body alters not only net
fluid balance but also osmotic equilibrium,
thereby changing the relative distribution of
fluids between the compartments. Reflex,

behavioral, and hormonal responses are three
essential routes to correct water and sodium
imbalances and maintain body fluid
homeostasis. Reflex and hormonal
mechanisms employ the autonomic nervous
system and endocrine responses to modify
renal losses of sodium and water in states of
dehydration, and to regulate vascular volume.
Behavioral responses include thirst, water
and salt intake. There have been several
excellent reviews (1,2) regarding body fluid
homeostasis. However, these reviews focused
on matured regulatory mechanisms in adults
for body fluid homeostasis. In this article, we
pay special attention to the development of
regulatory mechanisms during the early life
stage-fetal periods. Notably, a large number
of reports in the last two decades strongly

support the “Barker theory” (3), and it is

known that prenatal factors can cause

imprinting with long-term influence after birth,

and many diseases such as hypertension and

type II diabetes can be “programmed” in fetal

origin (4). Thus, it is of great importance to
understand the regulatory mechanism for body
fluid balance at early developmental stages. In
this review, we have focused on the hormonal,

renal, and behavioral regulation of body fluids
at fetal life in utero.
 

Hormonal regulation of fluid homeostasis
 

Fetal renin-angiotensin system

    Angiotensin precursors, enzymes, and
products in the fetus. The classic renin-
angiotensin system (RAS) consists of blood-
borne renin released from the kidney, which

acts on angiotensinogen (AGT) synthesized
predominantly in the liver to produce
angiotensin I. A dipeptide is released to
produce the octopeptide angiotensin II
(Ang II) by an enzyme, angiotensin-
converting enzyme (ACE) present in the
vasculature, particularly in the lung. Ang II
generated in the systemic circulation then
acts as an endocrine hormone causing
biological effects by binding to specific high

affinity receptors (at least two subtypes of
Ang receptors: AT1 and AT2). All
components of RAS (AGT, renin, ACE, AT1
and AT2) are expressed from early gestation
in humans (5) and animals (6).

    The expression of AGT gene can be detected
at early gestation in human fetal liver and
kidney (5) and at mid gestation in cord blood
(7), and AGT protein products can be identified
in the fetus. Fetal plasma AGT levels are
greater at late gestation than at early gestation,
indicating that RAS-mediated regulation in the
fetus is dependent on the gestational period.
Renin-containing cells have been demonstrated
in the walls of renal interlobar and afferent

vessels by 44 days of gestation (term: 145 days)
in fetal sheep. By 90-100 days of gestation,
renin is localized closer to the glomerulus, while after
131 days of gestation renin-containing cells are
distributed predominantly in the afferent
glomerular vessels (8). Studies from three
different models (individual isolated cells, organ
slice, and whole animals) suggest that renin
secretion is greater in the ovine fetus close to
term than at earlier gestation (9). These studies
suggest that there is an age-dependent increase
in fetal renin in the lamb with an increase in the
number of renin-containing cells and the renin
content per cell in the kidney. The mRNA for
ACE can be detected in a number of fetal
tissues, including the heart, liver, lung, and brain in the
early gestation period, and ACE is also present
in human and ovine mesonephros and the
metanephros (5).

 

    One of the major roles of Ang II in the fetus
is to maintain a high urine flow and thus ensure
adequate   volume of fetal fluids (amniotic and
allantoic in sheep). When Ang II is infused into the fetus there is an increase in urine flow and sodium excretion rates. In addition, elevated levels of Ang II in the fetus can increase blood pressure and cause diuresis at least from midgestation (10). Intracerebroventricular (icv ) injection of Ang II (11) elicits pressor responses in the near-term ovine fetus and results in compulsive drinking, and hormone release.

    Chronic increases in fetal plasma Ang II
suppress the secretion of prorenin and renin in
the fetal sheep kidney (12). The chronic
infusion of enalaprilat (ACE inhibitor) inhibits
fetal AGT in both early and late gestation.
Thyroid hormone and the renal nerves can
regulate RAS activity and both AT1 and AT2
receptor mRNA and protein expression (13,14)
in the fetus.

    In addition to its well-known roles in blood
pressure regulation and sodium/water
homeostasis, Ang II also acts as a growth factor
and cytokine. There is growing evidence that
Ang II may play a role during the development
of the placenta and fetal growth (15).

 

    Fetal angiotensin receptors. Ang II as the
main active peptide of RAS acts at specific
G-protein-coupled receptors, AT1 and AT2.
Several lines of evidence suggest that
fundamental differences exist in expression and
localization of both AT1 and AT2 receptors in the fetus. The expression of AT1 mRNA (5) is present in the fetus much earlier: at 27 days of gestation in ewe adrenal gland, at 8 weeks in human neocortex, and at embryonic day 17 in rat adrenal gland; whereas AT2 mRNA was detected as early as AT1 mRNA in the ovine fetus, at 5-6 weeks in the human fetus, and at embryonic day 15 in rat fetus. Furthermore, changes in AT1 and AT2 expression (16) are opposite. The level of AT1 is low in early gestation, before rising to a plateau and then increasing significantly close to term. AT2 expression, on the other hand, is highest at midgestation  and decreases thereafter. The mechanisms underlying  these ontogenic patterns of expression are not known.

   The central angiotensin receptors are well
developed and established in the last trimester
of gestation. Both AT1 and AT2 receptors have
appeared in the major structures in the
angiotensin-related central cardiovascular and
body fluid controlling pathways at the 0.7 of the
gestational age (17). Utilizing the in situ
hybridization technique, AT1 receptor mRNA
subtype appears in late gestation at embryonic
day 19 (E19) in forebrain areas involved in fluid

homeostasis and cardiovascular regulation in

rodents. AT2 receptor mRNA appears earlier at

E13 and is strongly but transiently expressed in

structures involved mainly in motor functions

and sensory integration. The appearance of the

brain receptors indicates the importance of the

role angiotensin plays in the maintenance of

fetal physiological  functions, including

cardiovascular and body fluid balance.
The questions whether AT1 and AT2 receptors

are  co-localized at the cellular level and which

mechanisms

mediate a possible AT1-AT2 receptor crosstalk still remain

to be resolved.

  

 

  

  

Most of Ang II-induced physiological responses appear

to be mediated by AT1 receptors. Endogenous Ang II, via activation of central AT1 receptors, exerts hypertensive

effects under normal conditions in the near-term ovine fetus. AT2 receptors do not appear to be involved, because icv injection of PD123319, the specific antagonist of AT2 receptor, did not affect Ang II-induced cardiovascular effects. This indicates that the central RAS and AT1, but not AT2 receptor, are critically involved in the regulation of arterial pressure in the near-term fetal sheep (18). In the

near-term ovine fetus, AT1 receptors but not AT2 receptors

(19) contribute to dipsogenic and pressor responses, as well as arginine vasopressin (AVP) release. Although little is known about the role of the AT2 receptor in the regulation of cardiovascular functions and body fluid balance, the high expression of AT2 receptors during fetal and early postnatal life implies an important role in cellular differentiation and organ development. Experiments using specific agonists and antagonists have provided new evidence for the involvement of AT2 receptors in the regulation of growth, cell proliferation, and apoptosis. More interestingly, the AT2 receptor has been shown to be reexpressed in the adult animal after cardiac and vascular injury or during wound healing, suggesting a role for this receptor in tissue remodeling, growth, or development.

Recent and concordant data suggested (20) that   overstimulation of AT2 receptors might be involved in 

cardiac and vascular hypertrophic processes, indicating that 

AT2 receptor may be involved in pathological processes in

some diseases. In light of this, these chronic changes may

also cause functional changes in body fluid regulation.

   Recent studies have shown that components of the RAS are candidates for a genetic link between low birth weight and adult diseases. Several genes from RAS have been found to be associated with cardiovascular diseases and insulin resistance after birth (14,15). This suggests that RAS may play an important role in the development of cardiovascular diseases and diabetes in fetal origin.  

Therefore, it should be interesting to test whether and to what extent the mediation by RAS mechanisms of body fluid

regulation is different in these experimental models.

 

Fetal aldosterone

  

The ovine fetal adrenal gland (21,22) is capable of

secreting aldosterone as early as about 40 days of gestation,

and plasma aldosterone concentrations over the last trimester of gestation are equal to or greater than levels present in maternal circulation. Under physiological conditions,

adrenocorticotropic hormone (ACTH) can stimulate

aldosterone production during middle gestation in the ovine

fetus. In both sheep and primates, secretion of aldosterone

by the fetal adrenal gland is low during most of gestation,

and only small increases are induced by stress or infusion

of ACTH. Although aldosterone concentrations in the fetus

are increased during stress, the usual stimuli of aldosterone

production are not able to produce consistent increases in aldosterone concentrations in the fetus in vivo.

   Blockade of the AT2 receptor (23), however, enables Ang II to stimulate aldosterone. This suggests that the inability of Ang II to stimulate aldosterone may be due in part to Ang II binding to the AT2 receptor and limiting the amount of Ang II available and/or antagonizing the effects of Ang II on the AT1 receptor. This suggestion is supported by the fact that in ovine fetuses more than 110 days of age, plasma aldosterone can be stimulated by Ang II, but high doses are required to produce moderate changes.

In the near-term ovine fetus, aldosterone can alter fetal urine electrolyte excretion, decreasing urinary sodium excretion and increasing potassium excretion (24), in response to intravenous aldosterone administration. Moreover, the amount of urinary sodium reabsorbed is regulated partly by aldosterone, which is physiologically active and induces increased urinary sodium reabsorption.

 

Meanwhile in late-gestation pregnant sheep, intra-amniotic aldosterone can be absorbed into the fetal circulation (24), and subsequently alter fetal urine composition. Fetal urine

sodium excretion is significantly decreased and potassium

excretion increased, although there is no change in urine

flow rate or fetal plasma electrolytes. When fetuses were

adrenalectomized at 120 days of gestation, removing the

endogenous source of cortisol and aldosterone, the rate of

fetal urine production and its composition are normal up to

140 days (25). Together, the data suggest: 1) ACTH- and

Ang II-mediated aldosterone production is relatively weaker

in fetuses than in adults, indicating that these regulatory

mechanisms in fetuses are immature; 2) both intra-amniotic

and fetal aldosterone in circulation play a partial role in

renal excretion in body fluid regulation in the fetus.

 

Fetal natriuretic peptides

  

Atrial natriuretic peptide (ANP), brain
natriuretic peptide (BNP) and C-type
natriuretic peptide (CNP) belong to a family
of hormones that have diuretic, natriuretic,
and vasodepressor activities in maintaining
blood pressure and fluid homeostasis in
adults. Proteins of natriuretic

peptides and their mRNA can be detected
during  embryogenesis at early developmental
stages. During embryogenesis in mice, ANP
and BNP mRNA appear at around 8-9 days
of gestation with a peak at 12.5 days (26). No
CNP expression has been detected in
developing hearts of either mouse or human
embryos (26,27). During development,

higher levels of ANP mRNA expression (26)
and ANP protein were detected in ventricles
than atria in rodents.

Conversely in fetal sheep, both of these are greater in the atria than ventricles throughout gestation (28). However, in human fetal ventricles, ANP mRNA is considerably higher than that in adult ventricles and tends to decrease with gestational age (27). Peptide levels of ANP and BNP in fetal ventricles have also been reported to be higher than those in the adult ventricle. In general, these studies indicate that the relative contribution of ventricular ANP is significantly greater in the embryo than in the adult, and in some species the ventricle is the predominant site of ANP and BNP expression during in utero development. As reported by Walther et al. (29), the natriuretic peptides appear to respond to similar stimuli, and to perform similar cardiovascular functions during development as they do in adults. The fetal natriuretic peptides (30,31) can   react to volume loading, hyperosmolality, and vasoconstrictors Ang II, phenylephrine, and endothelin in a manner similar to that in the adult heart; however, ANP and BNP respond differently to short-term and long-term volume load in the fetal circulation (32). Fetuses with Rhesus isoimmunization, and therefore long-term overload, exhibited significantly higher concentrations of ANP, whereas BNP was not influenced. In contrast, a short-term volume load by intravascular transfusion led only to a significant increase in BNP. Furthermore, infusion of ANP into the circulation of fetal sheep, albeit at supraphysiological concentrations

(increasing plasma levels from 163 to >2000 pg/mL), decreased arterial blood pressure, and elicited diuresis but not natriuresis (30). Therefore, the natriuretic peptide system appears to be functional by midgestation, to respond to volume change, and to regulate blood pressure and body fluid balance in the developing embryo.

The natriuretic peptides can also act as vasodilators in

the fetal–placental vasculature, regulating the blood supply

to the fetus, as demonstrated by expression of BNP and

CNP in the mouse placenta (26), and expression of ANP in

the human placenta by cytotrophoblast cells (33). 

Furthermore, ANP and BNP administered into the fetal placental circulation have been shown to inhibit the effect of 

vasoconstrictor agents.

Both ANP and BNP exert their biological actions by

binding to the natriuretic peptide receptor (NPR)-A,  

resulting in the generation of the second messenger cGMP,

while CNP binds natriuretic peptide receptor (NPR)-B with

high affinity. It is known that there are three different

natriuretic peptide-specific cell surface receptor proteins:

NPRA, NPRB, and NPRC. They are also known as NPR1,

NPR2, and NPR3, or as GC-A, GC-B, and the clearance

receptor, respectively, because both NPRA and NPRB

contain guanylyl cyclase (GC) catalytic activity. However,

NPRC functions without GC activity. To date, knowledge

about the natriuretic peptide receptor in fetuses is limited

(34). Expression of the GC-A receptor has been detected in the ovine fetal kidney and the vascular system. In contrast to ANP and BNP, CNP is unable to stimulate the production of cGMP in bovine embryonic aortic endothelial cells, but CNP is the most effective of the three peptides with respect to the stimulation of cGMP in fetal human vascular smooth muscle cells. Therefore, the GC-A receptor seems to be expressed in embryonic endothelial cells, whereas GC-B is located in the cell membrane of fetal smooth muscle cells. The binding was partly inhibited by excess of the ring-deleted ANP analogue, ANP(4-23) - a clearance receptor-specific peptide - indicating the presence and function of the third natriuretic peptide receptor. In the lungs of newborn piglets (35), ANP binds more strongly in veins than in arteries, indicating the presence of the GC-A receptor during maturation of the lung.

 

Fetal vasopressin and oxytocin

  

AVP and oxytocin (OT) are small nonapeptide hormones

that differ in only two of nine amino acids. AVP expressing

neurons have not been observed until 26 weeks of gestation in the human fetal suprachiasmatic nucleus (36). In the central nervous system (37), the genes for rodent AVP and OT appear as early as day 16 of intrauterine life. AVP transcripts were detected by in situ hybridization on day 16 in the supraoptic nucleus, and on day 21 in the hypothalamic suprachiasmatic nucleus in rodents. OT prohormone is not detected before day 16, while mature OT levels are low during gestation in rodents, and synthesis of OT is first detected by immunohistochemistry on the second day of postnatal life in rodents. In the murine fetal thymus, vasopressin (VP) transcription was detected on day 14-15, while OT transcripts (38) were detected by RTPCR as early as day 13. This indicates that VP and OT appear in the central nervous system at different stages of gestation. This difference in appearance in the brain suggests a difference in translation and precursor processing between hypothalamic neurons and thymic epithelial cells. Such discrepancy concerns the last enzyme in the processing of neurohypophysial peptides, peptidyl-glycine,

 

 

 

 

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