Prenatal Dexamethasone Programs Hypertension and Renal

Injury in the Rat

Luis A. Ortiz, Albert Quan, Francisco Zarzar, Arthur Weinberg, Michel Baum
AbstractDexamethasone is frequently administered to the developing fetus to accelerate pulmonary development. The
purpose of the present study was to determine if prenatal dexamethasone programmed a progressive increase in blood
pressure and renal injury in rats. Pregnant rats were given either vehicle or 2 daily intraperitoneal injections of
dexamethasone (0.2 mg/kg body weight) on gestational days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20.
Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 20% reduction in glomerular number
compared with control at 6 to 9 months of age (22 527509 versus 28 050561, P0.05), which was comparable to
the percent reduction in glomeruli measured at 3 weeks of age. Six- to 9-month old rats receiving prenatal
dexamethasone on days 17 and 18 of gestation had a 17% reduction in glomeruli (23 380587) compared with control
rats (P0.05). Male rats that received prenatal dexamethasone on days 15 and 16, 17 and 18, and 13 and 14 of gestation
had elevated blood pressures at 6 months of age; the latter group did not have a reduction in glomerular number. Adult
rats given dexamethasone on days 15 and 16 of gestation had more glomeruli with glomerulosclerosis than control rats.
This study shows that prenatal dexamethasone in rats results in a reduction in glomerular number, glomerulosclerosis,
and hypertension when administered at specific points during gestation. Hypertension was observed in animals that had
a reduction in glomeruli as well as in a group that did not have a reduction in glomerular number, suggesting that a
reduction in glomerular number is not the sole cause for the development of hypertension. (Hypertension. 2003;41:328334.)
Key Words: glucocorticoids hypertension, gestational glomerular filtration rate kidney

lucocorticoids are often administered to pregnant

women to accelerate fetal pulmonary maturation and
prevent respiratory distress syndrome.1 4 However, there is
evidence that prenatal administration of steroids may have
adverse effects on the developing fetus with consequences in
later life.59 Daily administration of prednisone, used as a
treatment for infertility in humans, resulted in infants that are
small for gestational age.5 Similar findings have been demonstrated in rodents.57
Administration of dexamethasone to pregnant rats produces adverse effects on the developing kidney.6,7,9 Rats born
to pregnant animals that received daily dexamethasone
throughout gestation had a 50% reduction in the number of
nephrons and a 30% reduction in glomerular filtration rate
when they were studied at 60 days of age.7 Rats exposed to
daily steroids during development also had significant hypertension at 2 months of age.6,7 Similarly, offspring of ewes
given prenatal glucocorticoids have hypertension as
adults.10 14 However, rats that were the product of mothers
receiving daily steroids had severe intrauterine growth retardation, which is also a predisposing factor for the development of hypertension and renal disease in later life.1518

We have recently examined the effect of 2 daily injections of prenatal dexamethasone (0.2 mg/kg per day) in
rats.9 We chose this dose to be comparable to that
administered to humans to accelerate pulmonary maturation. Two daily doses of dexamethasone did not produce
intrauterine growth retardation, unlike the above studies, in
which more doses of dexamethasone were administered.6,7
In addition, we found no effect on the numbers of rats in
the litter or on the length of gestation with prenatal
dexamethasone.9 Administration of dexamethasone on either days 15 and 16 or 17 and 18 resulted in a significant
reduction in nephrons when the rats were arbitrarily
studied at 2 months of age. Both the male and female rats
that received prenatal dexamethasone on days 15 and 16 of
gestation had hypertension, whereas only the male rats that
received dexamethasone on days 17 and 18 of gestation
had hypertension. Rats that received dexamethasone on
days 11 to 12, 13 to 14, 19 to 20, and 20 to 21 were
unaffected. Thus, there appears to be a critical time of
gestation that prenatal dexamethasone has its deleterious
effects that cause hypertension and a reduction in nephron
number.

Received August 1, 2002; first decision September 5, 2002; revision accepted November 18, 2002.
From the Departments of Pediatrics (L.A.O., A.Q., F.Z., M.B.), Internal Medicine (M.B.), and Pathology (A.W.), University of Texas Southwestern
Medical Center, Dallas, Tex.
Correspondence to Michel Baum, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas,
TX 75235-9063. E-mail Michel.Baum@UTSouthwestern.edu
2003 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org

DOI: 10.1161/01.HYP.0000049763.51269.51

328

Ortiz et al

Effect of Prenatal Dexamethasone on Rat Renal Development

A major shortcoming of our previous study was the fact

that rats that received prenatal dexamethasone were studied at
only one time point, which left several unanswered questions.
It was unclear if prenatal dexamethasone affected renal
development or caused a reduction in nephrons by programming the developing animal to have accelerated and progressive glomerular senescence. It was unclear whether the
hypertension was manifest in neonates and whether the
severity of the hypertension increased as the animal aged. It
was also unclear if the reduction in nephron number was the
sole cause for the hypertension. The present study examined
rats as neonates and at 6 to 9 months of age to address some
of these questions. We found that there is a reduction in
nephron number in neonatal rats but that only female rats
have an elevated blood pressure. In 6- to 9-month-old rats we
found that male rats that received dexamethasone on days 13
and 14, 15 and 16, and 17 and 18 of gestation have
hypertension but that a reduction in nephron number is not
the sole cause for the hypertension. Finally, we show that
prenatal dexamethasone can lead to glomerulosclerosis.

Methods
Animals
The pregnant rats arrived at our institution at least 2 days before
initiation of the study. Pregnant rats received either intraperitoneal
vehicle or dexamethasone (0.2 mg/kg body wt) daily on gestational
days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20. We
have previously shown that these dexamethasone protocols do not
affect litter size and do not cause intrauterine growth retardation.
Both male and female rats were studied. Prenatal dexamethasone
resulted in comparable differences from control rats in both male and
female rats in each of the protocols studied, and the results were
therefore combined except for blood pressure and renal histology.

Measurement of Glomerular Filtration Rate

Inulin clearance was performed in a fashion similar to that previously
described.9,19

Measurement of Blood Pressure

Blood pressure was measured with an IITC Model 179 Blood
Pressure Analyzer. Six-month-old animals were placed in a
Lucite tube, and a tail-cuff blood pressure cuff was inflated
several times daily on the 4 days before the actual measurement
of blood pressure. Three-week-old animals were placed in a
Styrofoam tube and trained as above and then returned to their
mothers. On the day of the actual blood pressure measurement,
there were at least 4 determinations, and the mean of these values
was used as the blood pressure for that rat.

Glomerular Number
Glomerular number was determined by using a variation of the
technique of Damadian et al, with significant modifications.9,20 22
Alcian blue is superior to india ink to stain glomeruli.20,22 Six- to
9-month-old rats received an intra-arterial infusion of 0.2 mL per
100 g body weight of 5% alcian blue (Aldrich Chemical Company)
in normal saline over a period of 1 minute, using a femoral arterial
catheter placed above the renal arteries after measurement of
glomerular filtration rate. A second 0.2 mL per 100 g body weight
bolus of alcian blue was then administered 5 to 7 minutes after the
first infusion. For the 3-week-old rats, an intra-aortic infusion of
2.5% alcian blue was administered. The kidneys were then removed
5 minutes after the second infusion and processed as recently
described.9

329

Figure 1. Effect of prenatal dexamethasone on number of glomeruli in 3-week-old rats. Pregnant rats were administered
dexamethasone (0.2 mg/kg body wt) or vehicle on gestational
days 15 and 16. At 3 weeks of age, the number of glomeruli
were counted by using alcian blue to stain the glomeruli followed by acid digestion. Number of glomeruli were reduced in
animals that received dexamethasone at 15 and 16 compared
with control. There were 8 rats in each group. Prenatal dexamethasone caused a significant reduction in the number of glomeruli at 3 weeks of age (P0.01).

Histology and Glomerular Size

Kidneys from 8-month-old control rats and rats that received prenatal
dexamethasone on 15 and 16 and 17 and 18 days of gestation or
vehicle were fixed in 10% phosphate-buffered formalin, embedded
in paraffin, sectioned at 4 m, and stained with hematoxylin and
eosin and with periodic acidSchiff stain. All of the glomeruli in a
cross section of kidney (100 to 200 glomeruli) from each animal
were examined for evidence of glomerulosclerosis. Glomerulosclerosis was defined as segmental or global collapse of the peripheral
capillary loops, often associated with capsular adhesions. There were
at least 3 kidneys from different animals examined in each group.
The kidneys were examined without operator knowledge of whether
they were from control or dexamethasone-treated rats.

Statistical Analysis
Values are expressed as meanSEM. ANOVA with post hoc
Student-Newman-Keuls test, unless otherwise noted, or unpaired
Student t test for studies examining 2 groups, was used to determine
statistical significance except for studies examining number of
sclerotic glomeruli, in which 2 analysis was used.
An expanded Methods section can be found in an online supplement available at http://www.hypertensionaha.org.

Results
Effect of Prenatal Dexamethasone on Glomerular
Number at 3 Weeks of Age
To determine if prenatal dexamethasone caused a reduction in
glomerular number in infant rats, we counted the number of
glomeruli in rats at 3 weeks of age. We examined the effect
of dexamethasone administered at days 15 and 16 of gestation, since this was previously determined to cause the
greatest reduction in glomerular number when the rats were
studied at 2 months of age.9 As shown in Figure 1, there was
a 14% reduction in glomerular number at 3 weeks of age
(P0.001). Thus, 3-week-old rats exposed to prenatal dexa-

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February 2003

Figure 2. Effect of prenatal dexamethasone on systolic blood

pressure in male and female rats measured at 3 weeks of age.
There was no significant difference in blood pressure in control
male rats and male rats that received prenatal dexamethasone
on days 15 and 16 of gestation. However, the difference in
female rats was significant (P0.001). There were at least 9 rats
in each group.

methasone have a reduction in nephron number consistent

with a reduction in nephron number in the perinatal period.

Effect of Prenatal Glucocorticoids on Blood

Pressure at 3 Weeks of Age
The effect of prenatal dexamethasone, administered at days
15 and 16 of gestation, on systolic blood pressure is shown on
Figure 2. We studied rats that were given dexamethasone on
days 15 and 16 of gestation because this was previously
shown to cause the greatest rise in blood pressure in rats
studied at 2 months of age. There was a small increase in
blood pressure in male rats that was not statistically significant. Female rats that received prenatal dexamethasone had a
higher blood pressure than female control rats (P0.01).

Effect of Prenatal Glucocorticoids on Number of

Glomeruli and Glomerular Filtration Rate at 6 to
9 Months of Age
The effect of prenatal dexamethasone on glomerular number
was determined in rats at 6 to 9 months of age that were
administered dexamethasone on days 11 and 12, 13 and 14,
15 and 16, 17 and 18, and 19 and 20. Rats were studied at
7.60.2, 7.60.3, 8.30.2, 8.60.1, and 7.60.3 months,
respectively. Control rats were studied at 8.40.2 months.
The 11 and 12 dexamethasone rats were slightly younger
(7.60.2 months) compared with control rats (8.40.2
months, P0.05). There was no difference in age between the
control rats and the other groups. As shown in Figure 3, the
results demonstrate that there was a 20% and 17% reduction
in the number of glomeruli when dexamethasone was administered on days 15 and 16 and days 17 and 18 of gestation,
respectively, compared with control rats (P0.05). These
results were virtually identical to those found when animals
were studied at 2 months of age.9

Figure 3. Effect of prenatal dexamethasone on number of glomeruli in 6- to 9-month-old rats. Pregnant rats were administered dexamethasone (0.2 mg/kg body wt) on gestational days
11 and 12, 13 and 14, 15 and 16, 17 and 18, 19 and 20, 20 and
21, or vehicle. Number of glomeruli was reduced in animals that
received dexamethasone either at 15 and 16 or 17 and 18 days
of gestation. There were at least 12 rats in each group.

As is shown in Figure 4A, there was no reduction in

glomerular filtration rate when the rats were analyzed at 6 to
9 months of age. There was also no difference in glomerular
filtration rate when factored per body weight as shown in
Figure 4B.

Effect of Prenatal Glucocorticoids on Blood

Pressure at 6 Months of Age
The effect of prenatal dexamethasone on systolic blood
pressure was determined in rats at 6 months of age that were
administered dexamethasone on days 11 and 12, 13 and 14,
15 and 16, 17 and 18, and 19 and 20 of gestation. There was
a difference in male and female rats at this age, as we found
in our previous study so male and female rats were analyzed
independently. The results are shown in Figure 5. Male rats
had an increase in blood pressure if administered dexamethasone on days 13 and 14, 15 and 16, and 17 and 18 days of
gestation. It should be noted that the 13 and 14 dexamethasone male group had an elevated blood pressure, whereas
there was no difference in the number of glomeruli
27 568387 in controls versus 28 545972 in the 13 and 14
male dexamethasone group. Thus prenatal dexamethasone
can increase blood pressure independent of a reduction in
glomerular number. There was no effect of prenatal dexamethasone on blood pressure in female rats.

Renal Histology
Histology of kidneys from an 8-month-old control male rat
and a male rat that received prenatal dexamethasone on days
15 and 16 of gestation are shown in Figure 6. Male rats that
had received prenatal dexamethasone on days 15 and 16 of
gestation had an increase in interstitial fibrosis and glomerulosclerosis. The number of glomeruli with evidence of

Ortiz et al

Effect of Prenatal Dexamethasone on Rat Renal Development

Figure 4. A, Effect of prenatal dexamethasone on glomerular

filtration rate (GFR). Glomerular filtration rate was measured in
anesthetized 6- to 9-month-old rats that received either prenatal
dexamethasone or vehicle. GFR was measured with [methoxy3H] inulin. There were at least 11 rats in each group. B, Effect of
prenatal dexamethasone on GFR factored per 100 g body
weight.

glomerulosclerosis is shown in the Table. As can be seen,

male rats in all groups had more sclerotic glomeruli than
female rats. The numbers of sclerotic glomeruli in both male
and female rats that received dexamethasone on days 15 and
16 of gestation were greater than in control rats (P0.001).

Discussion
The present study examined the effect of prenatal dexamethasone on glomerular number in neonatal and adult rats.
Although we had previously found that prenatal dexamethasone resulted in hypertension and a reduction in nephron
number at 2 months of age, this study extends the previous

331

Figure 5. Systolic blood pressures in 6-month-old rats that

received prenatal dexamethasone or vehicle. Blood pressure
was taken in trained rats using a tail cuff. Male rats (A) that
received prenatal dexamethasone on days 13 and 14, 15 and
16, and 17 and 18 had elevated blood pressure compared with
control rats. Female rats (B) were not hypertensive. There are at
least 10 male rats in each group. There were 8 female rats in
each group except days 11 and 12 and days 19 and 20, in
which there were 5 rats.

observations significantly and provides clues to how prenatal

dexamethasone reduces nephron number and produces an
elevated blood pressure in adult rats.
The fetus is normally protected from maternal steroids by
placental 11-hydroxysteroid dehydrogenase.23 Pregnant rats
exposed to carbenoxalone, an inhibitor of placental 11hydroxysteroid dehydrogenase, have offspring in which hypertension later develops.24,25 However, pregnant rats given
carbenoxolone during pregnancy but adrenalectomized to
protect the fetuses from maternal glucocorticoids were normotensive as adults.24 Pregnant rats that ingest a low protein
diet have low levels of 11-hydroxysteroid dehydrogenase
and have offspring that develop hypertension as adults.26,27
Pregnant rats that ingest a low protein diet but also receive

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February 2003

Figure 6. A, Female control kidney at 8 months of age showing

segmental sclerosis in 1 of 4 glomeruli. Note capillary collapse
and adhesion to capsule. The 3 other glomeruli show no significant abnormalities (periodic acid Schiff, 100). B, Male whose
mother received dexamethasone on days 15 and 16 of gestation. Segmental sclerosis is present in 3 glomeruli. There is interstitial fibrosis and tubular atrophy and a mild lymphocytic
infiltrate (periodic acid Schiff, 100).

metyrapone, an inhibitor of glucocorticoid synthesis, for the

first 14 days of gestation have offspring with normal blood
pressure.27 Dexamethasone is a poor substrate for 11hydroxysteroid dehydrogenase, which allows fetal exposure
to the administered glucocorticoid.
The mechanism for the hypertension resulting from limited
exposure to dexamethasone has yet to be elucidated. The
endowment of nephrons at birth has been proposed to be a
factor affecting blood pressure in adults.15,16,28 Human neoNumber of Sclerotic Glomeruli Divided by the Total Number Counted
Control

Prenatal
Dex 15 and 16

Prenatal
Dex 17 and 18

Male, n (%)

88/556 (15.8)

182/457 (39.8)*

122/650 (18.8)

Female, n (%)

22/612 (3.6)

46/342 (13.5)*

31/615 (5.0)

Gender

Dex indicates dexamethasone.

*P0.001, P0.09 vs control.

nates with intrauterine growth retardation have a reduced

number of nephrons28 and are predisposed to developing
hypertension as adults.1518 The mechanism mediating the
hypertension associated with congenital oligonephropathy is
controversial. A reduction in nephron number could impair
renal sodium excretion resulting in elevated blood pressure.15,16,28 However, it should be noted that in the present
study, there was no effect of prenatal dexamethasone on
glomerular filtration rate or when the glomerular filtration
was factored for body weight.
There is increasing evidence that the hypertension seen in
rat neonates born to mothers who ingested a low protein diet
during pregnancy is mediated by a dysregulation of the
renin-angiotensin system.29 31 Rats born to mothers that
ingested a low protein diet have an elevated plasma ACE
activity,29,30 and their blood pressure is normalized when
treated with an ACE inhibitor.29 Recent studies by Woods et
al31 demonstrated that renin mRNA and intrarenal angiotensin II levels were lower in rats that were the offspring of
mothers that ingested a low protein diet than control rats. This
group hypothesizes that reduced fetal and neonatal intrarenal
angiotensin II results in impaired renal development and the
reduced nephron number leads to hypertension in adult.31
There is also evidence that maternal dietary protein deprivation results offspring with upregulation of the bumetanidesensitive cotransporter and the thiazide-sensitive cotransporter, 2 transporters important in renal sodium absorption.32
Our data suggest that a reduction in nephron number is not
the sole factor causing the hypertension in rats exposed to
prenatal dexamethasone. Although there is by and large a
concordance with a reduction in nephron number and the
development of hypertension in rats exposed to prenatal
dexamethasone, there is only a 20% reduction in nephron
number in the 15 and 16 and 17 and 18 dexamethasone group.
It is hard to imagine that this small reduction in nephron
number is responsible for the hypertension. Furthermore,
unlike our previous study examining rats at 2 to 3 months of
age, we find that at 6 to 9 months, the 13 and 14 male
dexamethasone group had hypertension despite the fact that
there was no reduction in glomerular number in this group.
Thus this study demonstrates that there has to be other factors
besides a reduction in nephron number that causes the
hypertension with prenatal dexamethasone.
The other interesting factor relating to the hypertension
noted in this and our previous study was that there was a
difference in hypertension between male and female rats
exposed to prenatal dexamethasone. At 2 to 3 months of age,
only the female 15 and 16 prenatal dexamethasone group had
hypertension compared with 15 and 16 and 17 and 18 in the
male rats. In this study, at 6 months of age, the male rats that
received prenatal dexamethasone on days 13 and 14 also were
hypertensive. The female rats that received prenatal dexamethasone were not hypertensive at 6 months of age yet had
hypertension at 2 months. The reason for the amelioration in
hypertension is unknown. It is also of interest that only the
female rats at 3 weeks of age that received prenatal dexamethasone on days 15 and 16 of life had elevated blood
pressures, whereas the male rats did not. The reason for this

Ortiz et al

Effect of Prenatal Dexamethasone on Rat Renal Development

disparity is unclear at present but underlies the importance of

studying both genders.
In our previous and current study, we found that prenatal
dexamethasone administered on days 15 and 16 of gestation
resulted in a reduction in glomerular number compared with
control.9 There were several possible causes for the reduction
in glomerular number. The reduction in glomerular number
may result from intrauterine injury resulting in a paucity in
glomerular number from the time of birth or a progressive
reduction in glomerular number either caused by hypertension or programmed accelerated glomerular senescence. We
found a 14% reduction in glomerular number in 3-week-old
animals treated with dexamethasone at days 15 and 16 of
gestation and a 20% reduction in animals studied at 6 to 9
months of age. The fact that we were able to measure a
reduction in glomerular number in infant rats suggests that
the damage probably was due to an intrauterine insult. It
should be mentioned that the method used to measure
glomerular number in this study has not been validated in
young rats. The total number glomeruli in control 3-week-old
rats were less than that in adult control rats, even though
nephrogenesis is complete. Thus, it is likely that not all the
glomeruli in the 3-week-old rats were counted. Nonetheless,
we were able to demonstrate that there is a significant
reduction in glomeruli at this age.
There was also a difference in glomerulosclerosis between
our previous study and the current one. Focal segmental
glomerulosclerosis was rare at 2 months of age, and there was
no difference in control and dexamethasone-treated rats.
However, one of the most important findings in the current
study there was a statistically significant increase in glomerulosclerosis in both male and female rats who were exposed
to prenatal dexamethasone on days 15 and 16 of gestation.
This demonstrates that prenatal dexamethasone can cause
glomerular injury in rats.

Perspectives
This study demonstrates that prenatal dexamethasone administered at specific times of gestation results in a reduction in
glomerular number in infant as well as adult rats. The
hypertension was manifested at 3 weeks of age in female rats
but not male rats. In older rats, male rats that received
prenatal dexamethasone at specific times during gestation had
more severe hypertension than female rats. This study extends our previous findings to show that intrauterine exposure
to dexamethasone can program the rat to develop glomerulosclerosis. Finally, the hypertension was not solely due to the
reduction in glomerular number since the reduction was
modest and there were hypertensive males in the 13 and 14
dexamethasone group that did not have a reduction in
glomerular number. The relevance of this study to humans is
unclear at present. Although the 2 daily doses of dexamethasone were administered using a comparable dose per kg
body weight as used in humans to accelerate pulmonary
maturation, the development of the rat kidney is significantly
different than the human kidney. Nephrogenesis ends by
about 34 weeks of gestation in the human, but rats continue to
form new nephrons until approximately 1 week after birth.
Thus the time during gestation and when glucocorticoids

333

affect rat renal development may be quite different in the

human. Whether prenatal dexamethasone in humans increases the likelihood of developing hypertension and renal
disease is unknown.

Acknowledgments
This work was supported by National Institute of Diabetes and
Digestive and Kidney Disease grant DK-41612 (M.B.).

References
1. Ballard P, Granberg LP, Ballard RA. Glucocorticoid levels in maternal
and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome. J Clin Invest. 1975;56:1548 1554.
2. Crowley P. Promoting pulmonary maturity. In: Chalmers IM, Keirse
KJNC, eds. Effective Care in Pregnancy. Oxford, UK: Oxford University
Press; 1989:746 764.
3. NIH Consensus Development Panel on the Effect of Corticosteroids for
Fetal Maturation on Perinatal Outcomes. Effect of corticosteroids for fetal
maturation on perinatal outcomes. JAMA. 1995;273:413 418.
4. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid
treatment for prevention of the respiratory distress syndrome in premature
rats. Pediatrics. 1972;50:515525.
5. Reinisch JM, Simon NG, Karow WG, Gandelman R. Prenatal exposure to
prednisone in humans and animals retards intrauterine growth. Science.
1978;202:436 438.
6. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CRW. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet.
1993;341:339 341.
7. Celci G, Kistner A, Aizman R, Eklof A, Ceccatelli S, De Santiago A,
Jacobson SK. Prenatal dexamethasone causes oligonephronia, sodium
retention and a higher blood pressure in the offspring. Pediatr Res.
1998;44:317322.
8. Epstein MF, Farrell PM, Sparks JW, Pepe G, Driscoll SG, Chez RA.
Maternal betamethasone and fetal growth and development in the
monkey. Am J Obstet Gynecol. 1977;127:261263.
9. Ortiz LA, Quan A, Weinberg A, Baum M. Effect of prenatal dexamethasone on rat renal development. Kidney Int. 2001;59:16631669.
10. Dodic M, May CN, Wintour EM, Coghlan JP. An early prenatal exposure
to excess glucocorticoid leads to hypertensive offspring in sheep. Clin
Sci. 1998;94:149 155.
11. Dodic M, Peers A, Moritz K, Hantzis V, Wintour EM. No evidence for
HPA reset in adult sheep with high blood pressure due to short prenatal
exposure to dexamethasone. Am J Physiol Regul Comp Physiol. 2002;
282:R343R350.
12. Dodic M, Hantzis V, Duncan J, Rees S, Koukoulas I, Johnson K, Wintour
EM, Moritz K. Programming effects of short prenatal exposure to
cortisol. FASEB J. 2002;16:10171026.
13. Dodic M, Baird R, Hantzis V, Koukoulas I, Moritz K, Peers A, Wintour
EM. Organs/systems potentially involved in one model of programmed
hypertension in sheep. Clin Exp Pharmacol Physiol. 2001;28:952956.
14. Edwards LJ, Coulter CL, Symonds ME, McMillen IC. Prenatal undernutrition, glucocorticoids and the programming of adult hypertension. Clin
Exp Pharmacol Physiol. 2001;28:938 941.
15. Brenner BM, Chertow GM. Congenital oligonephropathy and the
etiology of adult hypertension and progressive renal injury. Am J Kidney
Dis. 1994;23:171175.
16. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure: less
of one, more the other? Am J Hypertens. 1988;1:335347.
17. Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size
and risk of hypertension in adult life. BMJ. 1990;301:259 262.
18. Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA,
Robinson JS. Fetal nutrition and cardiovascular disease in adult life.
Lancet. 1993;341:938 941.
19. Cogan MG, Liu F-Y. Metabolic alkalosis in the rat: evidence that reduced
glomerular filtration rather than enhanced tubular bicarbonate reabsorption is responsible for maintaining the alkalotic state. J Clin Invest.
1983;71:11411160.
20. Bankir L, Hollenberg NK. In vivo staining of the kidney with Alcian blue:
an adjunct to morphological and physiological studies. Renal Physiol.
1983;6:151155.
21. Damadian RV, Shwayri E, Bricker NS. On the existence of non-urine
forming nephrons in the diseased kidney of the dog. J Lab Clin Med.
1965;65:26 39.

334

Hypertension

February 2003

22. Gilbert T, Lelievre-Pegorier M, Malienou R, Meulemans A, MerletBenichou C. Effects of prenatal and postnatal exposure to gentamicin on
renal differentiation in the rat. Toxicology. 1987;43:301313.
23. Edwards CRW, Benediktsson R, Lindsay RS, Seckl JR. Dysfunction of
placental glucocorticoid barrier: link between fetal environment and adult
hypertension? Lancet. 1993;341:355357.
24. Langley-Evans SC. Maternal carbenoxolone treatment lowers birthweight and induces hypertension in the offspring of rats fed a proteinreplete diet. Clin Sci. 1997;93:423 429.
25. Lindsay RS, Lindsay RM, Edwards CRW, Seckl JR. Inhibition of 11Hydroxysteroid dehydrogenase in pregnant rats and the programming of
blood pressure in the offspring. Hypertension. 1996;27:1200 1204.
26. Langley-Evans SC, Phillips GJ, Benediktsson R, Gardner DS, Edwards
CRW, Jackson AA, Seckl JR. Protein intake in pregnancy, placental
glucocorticoid metabolism and the programming of hypertension in the
rat. Placenta. 1996;17:169 172.
27. Langley-Evans SC. Hypertension induced by foetal exposure to a
maternal low-protein diet, in the rat, is prevented by pharmacological

28.

29.

30.

31.

32.

blockade of maternal glucocorticoid synthesis. J Hypertens. 1997;15:

537544.
Mackenzie HS, Lawler EV, Brenner BM. Congenital oligonephropathy:
the fetal flaw in essential hypertension? Kidney Int Suppl. 1996;55:
S30 S34.
Langley-Evans SC, Jackson AA. Captopril normalizes systolic blood
pressure in rats with hypertension induced by fetal exposure to maternal
low protein diets. Comp Biochem Physiol. 1995;110A:223338.
Langley SC, Jackson AA. Increased systolic blood pressure in adult rats
induced by fetal exposure to maternal low protein diets. Clin Sci. 1994;
86:217222.
Woods LL, Ingelfinger JR, Nyengaard JR, Rasch R. Maternal protein
restriction suppresses the newborn renin-angiotensin system and
programs adult hypertension in rats. Pediatr Res. 2001;49:460 467.
Manning M, Beutler K, Knepper MA, Vehaskari VM. Upregulation of
renal BSC1 and TSC in prenatally programmed hypertension. Am J
Physiol, Renal Physiol. 2002;283:F202F206.