Hindawi Publishing Corporation
International Journal of Nephrology
Volume 2012, Article ID 760580, 15 pages
DevelopmentalProgramming of Hypertension
1Section of Neonatology, Department of Pediatrics, Hypertension and Renal Center of Excellence,
Tulane University Health Sciences Center, New Orleans, LA 70112, USA
2Section of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence,
Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Correspondence should be addressed to Ihor V. Yosypiv, email@example.com
Received 12 July 2012; Revised 18 September 2012; Accepted 21 October 2012
Academic Editor: Umberto Simeoni
Copyright © 2012 E. Chong and I. V. Yosypiv. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
A growing body of evidence supports the concept that changes in the intrauterine milieu during “sensitive” periods of embryonic
development or in infant diet after birth affect the developing individual, resulting in general health alterations later in life.
This phenomenon is referred to as “developmental programming” or “developmental origins of health and disease.” The risk
of developing late-onset diseases such as hypertension, chronic kidney disease (CKD), obesity or type 2 diabetes is increased in
infants born prematurely at <37 weeks of gestation or in low birth weight (LBW) infants weighing <2,500g at birth. Both genetic
viduals. A number of observations suggest that susceptibility to subsequent CKD and hypertension in premature or LBW infants is
mediated, at least in part, by reduced nephron endowment. The major factors influencing in utero environment that are associated
with a low final nephron number include uteroplacental insufficiency, maternal low-protein diet, hyperglycemia, vitamin A
deficiency, exposure to or interruption of endogenous glucocorticoids, and ethanol exposure. This paper discusses the effect of
premature birth, LBW, intrauterine milieu, and infant feeding on the development of hypertension and renal disease in later life
as well as examines the role of the kidney in developmental programming of hypertension and CKD.
Despite the availability of a number of treatment options
for hypertension, cardiovascular, and renal disease, the
prevalence, morbidity, and mortality of these diseases in
children and adults remain very high . Therefore, eluci-
dation of the causality and pathogenesis of these diseases is
critical. Studies by Widdowson and McCance in the 1960s
demonstrated that acceleration or retardation of the rate of
growth induced by malnutrition during early postnatal life
in rats led to distinct and different effects on anatomical,
physiological, and chemical development . In the 1980s,
studies by Barker demonstrated that systolic blood pressure
in older children is inversely related to their birth weight .
Around the same time, Brenner hypothesized that early
loss of nephron mass results in hyperfiltration of remaining
nephrons leading to subsequent hypertension, proteinuria,
and progressive kidney injury . These and subsequent
studies have provided initial evidence that a suboptimal in
utero environment may predispose or “program” an individ-
ual to an increased risk of developing renal or cardiovascular
disease in later life [5–9]. Although a number of potential
mechanisms underlying developmental origins of disease
have been proposed, a likely feature of many of these mecha-
nisms is interruption of normal kidney morphogenesis
resulting in a reduced number of nephrons and aberrant
development of the kidney vasculature . In this paper,
we discuss biological and molecular mechanisms linking
2International Journal of Nephrology
pre- and postnatal cues with nephron endowment, vascu-
larization of the developing kidney, and programming of
hypertension and renal disease during later life.
Development of the Kidney
Evidence derived from animal models and human studies
has demonstrated that the final number of nephrons can
be decreased by adverse prenatal conditions and predispose
to later kidney disease . New nephron formation during
embryonic kidney development is driven by the branching
ureteric bud (UB) that originates from the nephric duct on
the 5th week of gestation in humans (embryonic day E10.5
in mice) . Throughout its iterative branching, each UB
tip induces nephron progenitors to form nephrons, thus
forming the metanephric kidney . UB itself will form
the renal collecting ducts, calyces, pelvis, and ureter. The
mature human kidney has an average of ∼785,000 (range:
nephrons varies widely in humans, a kidney with a decreased
complement of nephrons may have less renal reserve to
adapt to dietary changes or compensate for renal injury.
Vascularization of the metanephros is synchronized with
epithelial nephrogenesis . In the mouse kidney, the first
arterioles are detected on E15-E16 (mouse gestation is 21
days) . Formation of the metanephros and renal vascu-
larization are directed by multiple gene networks [10, 12].
Aberrant expression or signaling of either the glial cell-
derived neurotrophic factor (GDNF)/Ret growth fac-
tor/receptor pair, transcription factors Six2 and Pax2, or the
renin-angiotensin system components are probably involved
in the programming of nephron development . Nephro-
genesis continues until 34–36 weeks of fetal life in humans.
Following acquisition of the full complement of nephrons
between 34 to 36 weeks of gestation in humans, new neph-
rons cannot be formed, and subsequent glomerular devel-
opment occurs via hypertrophy. Notably, faulty metanephric
organogenesis leads to reduced nephron endowment, abnor-
malities in renal vasculature, renal hypoplasia, hypertension,
and congenital anomalies of the kidney and urinary tract
(CAKUT), the major cause of renal failure in children .
Despite significant progress in our understanding of mor-
phological events and genetic programs that direct nephro-
genesis, the underlying molecular mechanisms that account
for a decreased final nephron number in response to subop-
timal in utero or perinatal environment and how alterations
in the kidney structure may impact disease risk in later life
areincompletely understood. Below, wediscussdisparities in
nephron endowment in low birth weight (LBW) and prema-
ture infants and explore the link of faulty nephrogenesis with
susceptibility to CKD and hypertension in later life.
3.Roles of LBW andPrematurityin
3.1. Introduction. LBW (birth weight <2500g) results from
either preterm birth (at <37 weeks of gestation) or intrauter-
ine growth restriction (IUGR). The term “IUGR” is used to
designate a fetus that has not reached its growth potential
used definition of IUGR is a fetus whose estimated weight is
below the 10th percentile for its gestational age (GA). IUGR
results in the birth of an infant who is small for gestational
age (SGA). In the absence of IUGR, preterm or full-term
infants are born appropriate for gestational age (AGA).
Importantly, IUGR is a frequent comorbidity of both pre-
term or term births .
3.2. Impact of LBW on Nephrogenesis, Blood Pressure, and
CKD. Animal and human studies have demonstrated the
association of LBW with later reduction in glomerular
number, renal dysfunction, and hypertension. For example,
glomerular number is directly correlated with birth weight,
whereas glomerular volume is inversely correlated with birth
weight in LBW infants . LBW infants have smaller
kidneys and decreased nephron number [16–20]. LBW SGA
infants exhibit a 30–35% reduction in nephron number
and a higher risk for developing hypertension [21–24]. The
observed reduction in nephron endowment is accompanied
by endothelial dysfunction that might be secondary to either
impaired angiogenesis, decreased production, or function of
nitric oxide [23, 24]. In a study of 56 LBW children with
IUGR at 4–6 years of age, systolic and diastolic BP were sig-
nificantly higher compared to the control group . These
observations have been confirmed by other studies [26–28].
In a 2012 meta-analysis, LBW was associated with increased
odds (1.2) for the development of hypertension . The
weight individuals are amplified with age . With regard
to the correlation between LBW and kidney injury, IUGR is
ESRD (1.58), and lower GFR (1.79) . A recent meta-
analysis demonstrates that the risk for developing protein-
uria, decreased kidney function, or ESRD is increased by 81,
79 and 58%, respectively, in LBW neonates . Proteinuria,
common among adults born as LBW infants [31, 32]. Adults
who were born extremely premature and with LBW have
an increased incidence of focal segmental glomerulosclerosis
(FSGS) with associated proteinuria . These findings are
in agreement with Brenner hypothesis that early loss of
nephron mass results in hyperfiltration of remaining neph-
rons leading to secondary FSGS, proteinuria, and progressive
kidney injury [4, 34, 35]. Unfortunately, it is not possible
to dissociate the effects of prematurity from LBW on the
outcomes observed in this study. A systematic review and
meta-analysis of observational studies by White et al. exam-
ined the association of LBW with the future risk of CKD
. This work assessed 31 cohort and case-control studies
that included data for birth weight and kidney function at
greater than 12 months of age. Significant associations were
uria, and ESRD. This analysis identified a consistent asso-
ciation between LBW and subsequent risk of CKD. Animal
models have also demonstrated the association of LBW
with later hypertension or renal injury. For example, LBW
International Journal of Nephrology3
due to ligation of uterine arteries in the rabbit model is
associated with reduced number of glomeruli in an offspring
. LBW induced by maternal dietary protein restriction
during gestation causes a 28-29% decrease in glomerular
number and a higher blood pressure at 8 weeks of age in
the rat . Restriction of maternal protein intake during
rat pregnancy results in LBW, elevated conscious mean arte-
rial pressure, reduced GFR, decreased number of glomeruli,
glomerulomegaly and no difference the total volume of all
glomeruli in adulthood . Collectively, multiple studies
demonstrate that LBW imparts a high risk of low nephron
endowment and glomerular hypertrophy. To sustain ade-
quate kidney function following completion of nephrogene-
sis, remaining glomeruli will need to undergo compensatory
hypertrophy, an adaptation that may result in an accelerated
loss of functioning nephrons. Resulting decreased filtration
surface area may lead to subsequent hypertension via limita-
tion in renal sodium excretion. In view of a possible causal
relationship between LBW, nephron endowment, hyperten-
sion, and CKD, continued assessment of the mechanisms
associated with fetal life events are warranted to further
define this risk.
3.3. Impact of Prematurity on Nephrogenesis, Blood Pressure,
and CKD. More than 12% of infants in the United States are
born preterm (at <37 weeks of gestation), illustrating that
many neonates enter extrauterine life during active nephro-
genesis . Determination of the effect of prematurity
per se on renal consequences and developmental program-
ming of hypertension and CKD in humans is hampered by
the fact that many premature neonates that exhibit IUGR
have multiple health problems and are exposed to various
medications that may influence nephrogenesis. For example,
acutekidney injury (AKI) is observed in 8%–24% of preterm
neonates . Use of NSAIDs, aminoglycoside antibiotics,
and diuretics have also been shown to potentially hamper
nephrogenesis in prematurely born neonates . An
autopsy study of premature AGA neonates demonstrated
that prematurity alone, without IUGR, is associated with
lower radial glomerular counts (RGCs) compared with full-
with gestational age  (Table 1). RGCs in preterm infants
with AKI surviving >40 days were lower than in those
without AKI, whereas glomerular surface area was highest
in preterm neonates without AKI . Thus, nephrogenesis
AKI. In addition, preterm birth results in glomerular hyper-
trophy that may lead to hyperfiltration and subsequent renal
in premature infants does not further increase the risk of
poor renal growth or development of subsequent hyperten-
sion. In this regard, ultrasonography performed at 20 years
of age showed decreased kidney size in individuals born pre-
maturely at <32 weeks of gestation compared with full-term
controls and no difference in kidney size between SGA and
AGA individuals . Thus, either IUGR had no effect on
renal size in premature individuals or the lack of significant
differences might be due to insufficient power of this study.
In contrast, a study by Drougia et al. reported that kidney
length (adjusted for body weight and surface area) is reduced
in children who were born premature and SGA compared
with those who were premature and AGA . Premature
ment in kidney growth with age at 18 months of age . Of
prematureSGA than prematureAGA infants, suggesting that
19 years of age was increased in premature neonates born at
<32 weeks of gestation, but this was not apparently related
to the extent of IUGR . Similar observations were made
by Singhal et al. showing that blood pressure measured at 15
years of age did not differ among full-term, preterm AGA,
or preterm SGA (with IUGR) individuals . However,
endothelial-dependent vasodilation was reduced in preterm
SGA compared with preterm AGA or full-term individuals.
These results do not support the hypothesis that prematurity
a large Swedish study reported an inverse association of
systolic blood pressure measured at 18 years of age with GA
alone or with GA adjusted for birth weight (IUGR), but not
with birth length adjusted for GA . The inverse associa-
tion of GA with blood pressure was larger when adjusted for
birth weight, suggesting that IUGR might further increase
the risk of subsequent hypertension in premature infants.
The authors proposed that the rate of accretion of fetal soft
tissue mass rather than of linear bone growth is associated
with programming of elevated blood pressure. Kistner et al.
reported that systolic ambulatory blood pressure was higher
in adult woman born preterm AGA compared with either
term AGA or term SGA . Mean blood pressure and
brachioradial artery pulse wave velocity, and hence arterial
stiffness, were higher in premature SGA compared with pre-
mature AGA or term AGA infants when measured at 8 ± 1.7
years of age . The discrepancies in findings among these
studies may relate to differences in methodologies used to
measure blood pressure. Overall, available evidence indicates
that reduced nephron endowment after premature birth
does not necessarily result in hypertension later in life. It is
conceivable that elevated blood pressure may ensue only
when the functional reserve of remaining nephrons is
depleted below certain threshold.
A lower GFR and a higher prevalence of microalbumin-
uria were observed in SGA compared with AGA premature
infants born at <32 weeks of gestation, suggesting that the
presence of IUGR might further increase the risk of progres-
In accord with these findings, GFR measured by inulin clear-
ance at mean age of 7.6 years in children was lower in SGA
compared with AGA premature individuals . However,
urine albumin/creatinine ratio or blood pressure did not
differ. Studies in nonhuman primates demonstrate that pre-
maturity without IUGR can cause abnormal kidney devel-
opment . Preterm baboons delivered at 125 (term = 185)
days of gestation were studied after 21 days of extrauterine
life and compared to GA-matched controls delivered and
4 International Journal of Nephrology
Table 1: Effect of prematurity alone or prematurity with IUGR on postnatal kidney growth, morphology, and programming of renal
dysfunction and blood pressure.
Study designSummary of reported findings
Decreased RGC in premature AGA versus term
Increased mesangial tuft area and Bowman’s
capsule area in preterm surviving >40 days
without RF versus term or preterm surviving
<40 days with or without RF
Rodr´ ıguez et al. USA
An autopsy study of 56 extremely premature
infants (n = 42 AGA, and n = 14 SGA)
Keijzer-Veen et al.  Netherlands
Determination of renal size at 20 years of age by
ultrasonography in 81 individuals born preterm
AGA, (n = 29), SGA (n = 22), or term (n = 30)
Determination of kidney length at 2 years of
chronologic age in 466 children (n = 223 AGA
and n = 243 SGA)
Determination of kidney volume by
ultrasonography at birth and at 18 months of age
in preterm or term SGA (n = 178) versus term
AGA (n = 717)
Determination of kidney morphology on autopsy
in 28 preterm neonates at 2–68 days after birth
and 32 stillborn gestational controls
Decreased kidney size in both preterm AGA and
SGA versus term. No difference in kidney size
between AGA and SGA preterm
Drougia et al. Greece
Decreased kidney length in preterm SGA (<36
weeks of GA) versus preterm AGA
Schmidt et al. Denmark
Reduced kidney volume at birth and 18 month
of age in premature AGA versus term AGA and
in preterm SGA versus preterm AGA.
Sutherland et al. Australia
Higher percentage of enlarged glomeruli in
preterm versus controls, no difference in kidney
weight in preterm SGA versus preterm AGA
Hinchliffe et al. UK
Determination of total glomerular number and
volume in stillborn AGA and SGA neonates, in
liveborn AGA, and SGA infants who died within 1
year of birth
Decreased glomerular number in SGA versus
AGA in both stillborn and those who died
within 1 year after birth, no difference in
Gubhaju et al. Australia
Determination of kidney and glomerular size,
glomerular density, glomerular morphology and
number, and number of glomerular generations
in preterm baboons studied after 21 days of
extrauterine life versus GA-matched controls
Larger kidneys, decreased glomerular density,
enlarged glomeruli, shrunken glomerular tuft,
and cystic Bowman’s space in preterm versus
No difference in total number of glomeruli or
number of glomerular generations
Stelloh et al. USA
Determination of the effect of preterm delivery at
1-2 days prior to term birth in mice on glomerular
number, blood pressure, measured GFR, and
urine albumin/creatinine ratio at 5 weeks of age
A 20% decrease in glomerular number,
increased blood pressure, lower GFR and higher
urine albumin/creatinine ratio in preterm versus
Keijzer-Veen et al.  Netherlands
Determination of blood pressure at 19 years of
age in 422 individuals with GA < 32 weeks and in
174 individuals with GA > 32 weeks and birth
Increased prevalence of elevated blood
pressure in GA < 32 weeks versus GA > 32 weeks
not related with IUGR, increased postnatal
weight gain and weight at age of 19 affected the
risk for hypertension
Singhal et al.  UK
Determination of blood pressure and
vasodilation (EDV) in preterm SGA (n = 72),
preterm AGA (n = 144), and term AGA (n = 61)
individuals at age 13–16 years
No difference in blood pressure among all
groups and reduced EDV in preterm SGA versus
preterm or term AGA
Leon et al. Sweden
Record linkage study of 165;136 men studied at
mean age of 18 years
Inverse association of blood pressure with GA
alone or with GA adjusted for birth weight
(SGA) and increased inverse association of
blood pressure in SGA versus AGA
Kistner et al.  Sweden
Determination of systolic ambulatory blood
pressure (ABP) at a mean age of 26 ± 2 years in
woman born term SGA (n = 18), with term AGA
(n = 17), and preterm AGA (n = 14)
Determination of mean blood pressure and
brachioradial artery pulse wave velocity (PWV) in
ex-preterm SGA (n = 15), preterm AGA (n = 36),
and term AGA (n = 35) children at 8 ±1.7 years
Higher systolic ABP in preterm AGA versus term
AGA or term SGA, no difference in term SGA
versus term AGA
Cheung et al. China
Higher mean blood pressure and PWV in
preterm SGA versus preterm or term AGA
International Journal of Nephrology5
Table 1: Continued.
Determination of GFR and urine
albumin/creatinine ratio at 19 years of
age in individuals with GA < 32 weeks
SGA (n = 215) or AGA (n = 207)
Single-center prospective cohort study
Determination of GFR measured by
inulin clearance at mean age of 7.6 ±1.3
years in preterm SGA (n = 23), AGA
(n = 11), and preterm with EUGR
(n = 16)
Summary of reported findings
Keijzer-Veen et al. Netherlands
Decreased GFR and increased prevalence of
high albumin/creatinine ratio in preterm
SGA versus AGA
Bacchetta et al.  France
Lower GFR in SGA versus AGA and in
EUGR versus AGA, no difference in urine
albumin/creatinine ratio or in blood
pressure among the groups
RGC: radial glomerular count, RF: renal failure, GA: gestational age, SGA: small for GA, AGA: appropriate for GA, GFR: glomerular filtration rate, EUGR:
extrauterine growth retardation.
studied at 146 (125 + 21) days of gestation. Kidneys of pre-
term baboons were larger, had decreased glomerular density,
enlarged glomeruli, a cystic Bowman’s space, and shrunken
glomerular tuft, whereas the number of glomerular genera-
tions and total glomerular number did not differ . The
proportion of abnormal glomeruli ranged from 0.2 to 18%,
suggesting that preterm birth may not adversely impact kid-
ney development equally. Since premature baboons received
antibiotics after birth (gentamicin and ampicillin), it is con-
ceivable that the glomerular changes observed in this group
resulted from antibiotic-induced nephrotoxicity. Because
kidney development in nonprimate experimental models
differs from that of primates (e.g., nephrogenesis continues
postnatally in the mouse or rat), observations made in this
study are more relevant for human disease. Indeed, preterm
infants also have a higher percentage of enlarged glomeruli
compared with stillborn gestational controls . However,
there was no difference in kidney or body weight at autopsy
between SGA and AGA infants. This may be due to catch-
up growth of the kidney postnatally after preterm birth in
SGA neonates or to an insufficient power of the study due
to a small number of preterm SGA infants (6 of 28). In addi-
tion, the width of the nephrogenic zone was lower in pre-
term than gestational control infants, implying a decreased
capacity to form new nephrons in extrauterine environment
. Stillborn SGA infants or liveborn SGA infants who
died within a year of birth had fewer nephrons than control
stillborn AGA infants or control AGA neonates who died
within a year of birth, respectively . These findings sug-
number. Experimental study in mice demonstrated that
premature delivery at 1-2 days prior to term birth caused a
20% decrease in glomerular number and resulted in elevated
blood pressure, a lower measured GFR, and higher urine
albumin/creatinine ratio at 5 weeks of age compared to full-
term controls . Since these effects of prematurity cannot
be explained by unfavorable intrauterine conditions, it is
to premature termination of nephrogenesis by depriving the
developing kidney from maternal factors essential for kidney
development. Some observational studies in humans seem
to agree with this possibility [39, 41, 45]. Collectively, these
observations suggest that: (1) preterm kidneys may have
fewer functional nephrons, thereby increasing vulnerability
to impaired renal function in both the early postnatal period
and later in life and (2) compensatory mechanisms in sur-
viving preterm infants include glomerular hypertrophy that
could lead to hyperfiltration. Overall, association of prema-
turity alone without IUGR with later kidney dysfunction
or hypertension in children is subtle and requires further
3.4. Can Programmed Hypertension Be Dissociated from
Reduced Nephron Number? Even though the combination of
Barker and Brenner hypotheses offers an explanation for the
association of a reduced nephron number with hypertension
and renal disease, no definitive proof has been found that
low nephron endowment per se causes increased risk for
hypertension or renal injury. Moreover, some animal studies
demonstrate that reduced nephron number per se does not
appear to mediate development of later hypertension. In a
study by Hoppe et al., nephron number as well as conscious
mean arterial pressure was reduced on postnatal day 135
in rats born to mothers fed a low-protein isocaloric diet
throughout gestation and postnatally compared to rats fed
a normal protein diet . The authors proposed that the
apparent blood pressure-lowering effect of life-long dietary
protein restriction may be due to effects mediated during the
postnatal period. Although the nature of postnatal factors
sure remains to be elucidated, one potential mechanism may
involve a shift in the pressure natriuresis relation towards
lower mean arterial pressure. Because nephrogenesis contin-
ues postnatally in the rat, Wlodek et al.  hypothesized
that nephron endowment and blood pressure of male
ulated by altering the postnatal (lactational) environment by
cross-fostering. Uteroplacental insufficiency, created by liga-
tion of uterine arteries on gestational day 18 (of 21), resulted
in impaired mammary gland function, a twofold reduction
in litter size, neutropenia, and adult hypertension. Cross-
fostering of these newborn pups onto mothers with normal
lactation prevented the nephron deficit and hypertension
. In contrast, pups born to mothers without ligation of
6 International Journal of Nephrology
the spontaneously low litter size observed in uteroplacental
insufficiency group and then cross-fostered at birth onto
mothers subjected to ligation of uterine arteries had no
nephron deficit but developed hypertension. The authors
corrected by providing normal lactation postnatally, and (2)
programmed hypertension can be dissociated from reduced
nephron number in uteroplacental insufficiency model.
These findings do not prove a causal relationship between
restoration of nephron endowment by improved postnatal
lactation and prevention of hypertension. It is conceivable
that optimized postnatal nutrition affected development of
the cardiovascular system or other factors (e.g., vasoactive
factors) that regulate blood pressure to prevent the onset
of hypertension independent of the effect on nephrogenesis.
Given that 80% of nephrons in the rat kidney form in the
first 10 days after birth, it is equallypossible that the nephron
deficit in offsprings of placentally restricted mothers was
generated during embryonic or early postnatal period .
New studies examining nephron number at birth and at spe-
cific postnatal time points are required to determine whether
nutritional rescue prevented nephron deficit or overcame a
preexisting deficit by “accelerating” postnatal nephrogenesis.
Together, these observations demonstrate that the postnatal
environment is also important in determining the outcomes
of developmental programming and that reduced nephron
number per se does not appear to mediate all programmed
hypertension. In addition, there are significant differences
between reduced nephron number early in life and loss of
nephrons later in life (e.g., kidney donation as an adult) in
terms of later renal disease or hypertension. Studies in rats
showed that unilateral nephrectomy during the later stages
of kidney development (when nephrogenesis still continues)
results in a higher GFR when compared to nephrectomy
during early adulthood (after completion of nephrogenesis)
. This presumably reflects much more vigorous compen-
satory mechanisms in the developing organism.
3.5. Impact of Gestational Environmental Factorson Renal and
Cardiovascular Outcomes. A growing body of evidence indi-
cates that developmental programming of blood pressure
(eg., CKD and gestational diabetes), undernutrition, dietary
tion (Table 2). Uteroplacental insufficiency, one of the most
common causes of IUGR, occurs in 7–10% of pregnancies
smoking, or maternal undernutrition [59–61]. Approxi-
mately 25% of pregnant women smoke throughout their
pregnancy, and smoking is one of the most modifiable risk
factor for IUGR in developed economies [59–61]. Exposure
to cigarette smoking in utero correlates with an increase in
BP in the offspring in adulthood [62, 63]. Nicotine, the
main component in cigarettes, induces vasoconstriction and
decreases placental blood as well as oxygen delivery to the
fetus resulting in aberrant fetal vascular development [93,
94]. In addition, maternal smoking stimulates production of
the vasoconstrictor and thromboxane A2 . Renal renin
expression was noted to be decreased in animal models
of uteroplacental insufficiency, leading to decreased RAS
activity during nephrogenesis . Additional factors shown
to be associated with decreased nephron endowment and
hypertension in children include maternal use of cocaine or
as hydronephrosis, a congenital anomaly commonly seen in
fetal alcohol syndrome [65, 66]. Another mechanism impli-
cated in renal dysfunction associated with prenatal ethanol
exposure includes an increase in cell death in the region of
the developing nephric duct and in Na-K-ATPase activity
in the renal cortex . Use of indomethacin for tocolysis
is associated with fetal renal impairment with oliguria and
oligohydramnios [95–97]. Studies have shown that exposure
to NSAIDS in utero resulted in decreased GFR secondary
to reduction in renal blood flow, abnormal glomerular, and
tubular development . The observations that a number
of perinatal insults such as maternal malnutrition, exposure
to medications or toxins during pregnancy, or uteroplacental
insufficiency have been associated with later hypertension or
3.6. Mechanisms That Mediate the Impact of Gestational Envi-
ronmental Factors on Renal and Cardiovascular Outcomes.
Although our understanding of the underlying mechanisms
implicated in programming of hypertension and CKD is far
from complete, experimental models have provided certain
mechanistic information. Animal models evaluating the
effects of a low-protein diet during pregnancy have shown
that offsprings with reduced number of glomeruli who
develop hypertension in adulthood have altered expression
of genes controlling metanephric organogenesis [35, 55, 56,
77, 83, 98–102]. The critical role of mutations in genes that
direct metanephric organogenesis in developmental pro-
gramming of renal dysfunction and blood pressure is
development in animal models, are associated with reduced
renal volume in humans and may therefore associate with a
reduced number of nephrons [103, 104]. Exposure to mater-
nal low-protein diet in utero in the rat causes hypertension
associated with microvascular rarefaction (reduced density
of arterioles and capillaries) and decreased angiogenesis
[105, 106]. Notably, microvascular rarefaction is associated
with hypertension . Another mechanism by which
maternal low-protein diet may cause renal hypoplasia in an
offspring is by increasing concentration of glucocorticoids
via downregulation of the placental steroid-metabolizing
enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β
HSD2) . Decreased 11β HSD2 activity increases endoge-
nous cortisol levels and leads to an increased plasma volume
secondary to enhanced renal sodium retention and eventu-
ally to salt-sensitive hypertension . The RAS plays an
important role in fetal growth restriction and the develop-
ment of hypertension in response to maternal low-protein
diet. Decreased nephron endowment and glomerular hyper-
trophy are accompanied by suppression of the newborn
International Journal of Nephrology7
Table 2: Effect of environmental factors on kidney development and programming of renal dysfunction and blood pressure.
Maternal low-protein diet
Maternal cigarette smoking
LBW, decreased nephron number, and salt-sensitive hypertension
Decreased nephron number
Decreased nephron number and hypertension
[16, 38, 55–58]
Vitamin A deficiency
Rat-decreased birth weight and hypertension Rat-decreased nephron number
Rat-hypertension in an offspring, children-increased responsiveness of blood
pressure to changes in dietary salt intake
Decreased GFR and reduced number of nephrons hypertension
Abnormal glomerular and tubular development
Renal tubular dysgenesis and hypotension
Decreased nephron number and hypertension
Obesity and increased insulin resistance
Protect against insulin resistance
Decreased nephron number and proteinuria, hypertension
[56, 68, 77–79]
[36, 52, 90–92]
LBW: low birth weight, GFR: glomerular filtration rate, NSAIDS: nonsteroidal anti-inflammatory drugs, ACEi: angiotensin-converting enzyme inhibitors,
ARBs: angiotensin receptor blockers, COX-2: cyclooxygenase-2, and GR: glucocorticoid receptor.
intrarenal RAS, system essential for normal kidney devel-
opment [99–102]. In addition, maternal low-protein diet
increases the risk of salt-sensitive hypertension .
Observed salt sensitivity in an offspring may be due to
increased expression of Na-K-2Cl (NKCC2) cotransporter in
the thick ascending limb of the loop of Henle or decreased
duct [108, 109]. Administration of ouabain, a Na-K-ATPase
ligand, to these rats abolished apoptosis and increased cell
proliferation in the metanephric blastema [110, 111]. Oxida-
tive stress and subsequent inflammation may be another
important factor in programming hypertension. In this
regard, maternal low-protein diet in the rat elicits oxida-
tive stress and inflammation in the offspring . It is
postulated that low-protein diet results in a relative defi-
ciency of nitric oxide (NO), a powerful vasodilator, and that
supplementation with L-arginine, a NO donor, may be pro-
tective [58, 113–115]. Supplementation of lipid peroxidation
inhibitor in pregnant rats fed low-protein diet prevents an
elevation in blood pressure and improves vasodilatation and
microvascular rarefaction in the offspring .
The importance of glucocorticoids in nephron endow-
ment and programming of hypertension is demonstrated
by the findings that administration of exogenous glucocor-
ticoids to pregnant rats leads to reduced nephron number,
possibly via downregulation of UB branching morphogene-
sis genes and results in hypertension in adult life [68, 69, 78,
the first trimester in sheep leads to normal birth weight with
[117, 118]. Observed programming of high blood pressure
may be due to aberrant UB branching morphogenesis and
decreased glomerulogenesis that may be secondary to alter-
ations in the intrarenal RAS . Supplementing maternal
diet with omega-3 fatty acid prevents dexamethasone-
induced hypertension, hyperleptinemia, and upregulation of
renal Na-K-ATPase activity in the offspring, thus providing
an opportunity for potential therapeutic interventions .
Given that exposure to dexamethasone in animal models of
IUGR stimulates activity of Na+-H+exchanger in the proxi-
mal tubules; enhanced tubular reabsorption of sodium may
play a role in developmental programming of hypertension
. An important role for estrogen in programming of
replacement in ovariectomized animals normalizes blood
pressure in animal model of IUGR . Administration of
angiotensin (Ang) II to IUGR rats potentiates the observed
increase in BP, suggesting that the RAS is important in
the pathogenesis of hypertension in this model. IUGR rats
of both sexes have decreased levels of vascular endothelial
growth factor (VEGF), a growth factor critical for normal
nephron endowment .
Increased maternal salt intake can result in renal struc-
tural and functional changes similar to those produced by
gestational protein restriction [70, 71]. Both excessively high
and low maternal sodium intakes during pregnancy in the
rat cause aberrant expression of genes critical for normal
metanephric organogenesis and reduce the final number of
high maternal salt intake during gestation in bradykinin B2
receptor-deficient mice provides proof of the principle that
environmental factors may act in concert with single-gene
mutations to cause aberrant kidney development .
8 International Journal of Nephrology
Experimental and observational studies suggest that
premature birth can also adversely affect both vascular
development and function . Reduced density of arte-
rioles and capillaries is associated with hypertension .
The importance of vascularization in programming of later
hypertension is supported by the findings that reduced
retinal vascularization observed in the preterm infants is
. Neonates of mothers with preeclampsia (gestational
hypertension) have increased aortic intima-media thickness
and elevated serum triglyceride levels . LBW is asso-
ciated with an increased arterial wall stiffness in adoles-
cents and adults [47, 125]. Impaired endothelial-dependent
arterial relaxation, an early marker for the development of
hypertension, may persist to adult life in LBW infants [23,
24]. These events may result in an increase in cardiovascular
risk later in life. Given that deficiency of elastin in the arterial
wall is the major determinant of arterial wall stiffness and
decreased elastin content may be a likely cause of stiffer
arteries and an increased risk of hypertension and cardiovas-
cular disease in later life .
Oxidative stress has been implicated in developmental
programming of hypertension. The fetus is hypoxic under
physiologic conditions compared with the adult. Blood
oxygen content increases abruptly after birth, leading to the
generation of oxygen-free radicals . Premature infants
have immature antioxidant systems to respond to oxidative
stress occurring during the transition to extrauterine life or
need for oxygen therapy because of lung immaturity .
Gestational maternal protein restriction in rats results in
impairment of antioxidant defenses as well as shorter aortic
telomere length characteristic of vascular atherosclerosis,
thus providing a possible mechanistic link between develop-
mental insults and cardiovascular disease . Our under-
standing of the mechanisms underlying possible long-term
consequences of aberrant vascular structure and function,
oxidative stress, and developmental kidney morphology in
susceptible individuals is inadequate. Together, studies in
animal models indicate that a number of specific pertur-
bations are associated with aberrant nephron endowment
in response to gestational environmental factors and subse-
quent risk of hypertension or CKD. These alterations include
altered expression of genes controlling metanephric organo-
genesis, aberrant cell proliferation, survival and differenti-
ation, fetal exposure to higher glucocorticoid levels, renal
oxidative stress and inflammation, and increased expression
of renal transporters promoting salt retention.
3.7. Impact of Postnatal Environmental Factors on Renal and
Cardiovascular Outcomes. Emerging data demonstrate that
the early postnatal period is an additional developmental
phase that is also susceptible to developmental program-
ming. Rapid postnatal weight gain in LBW neonates is asso-
ciated with childhood hypertension . LBW infants who
gained weight rapidly during childhood (1 to 5 years) had
the highest blood pressure . In a mice model, feeding
high-fat diet after caloric restriction is associated with lipid
accumulation and insulin resistance . Children with
extrauterine growth restriction (EUGR) (AGA with weight
or height below the 10th percentile at discharge from NICU)
controls at mean age of 7.6±1.3 years, suggesting that EUGR
is a risk factor for subsequent impairment of renal function
in premature neonates . Premature neonates are also
at risk of iatrogenic injury from administration of steroids,
NSAIDS/COX-2 inhibitors or nephrotoxic antibiotics post-
natally [81, 82]. Exposure to COX-2 inhibitors during neph-
rogenesis results in low nephron endowment and hyper-
tension at birth that persists through adulthood .
Administration of COX-2 inhibitor to rats with altered renal
development induces a greater renal vasoconstriction [84,
85]. Use of glucocorticoids is a standard of care to accelerate
lung development in preterm births. Recent studies demon-
strate that premature Caucasian individuals carrying a
to be associated with higher sensitivity to glucocorticoids,
develop abdominal adiposity and insulin resistance when
exposed to antenatal glucocorticoids [86, 87]. In contrast,
carriers of the GR ER22/23K variant, noted to be associated
with lower sensitivity to glucocorticoids, are protected
against insulin resistance after preterm birth [86, 87]. Lim-
itations of the study by Finken et al. include a small number
of subjects heterozygous for N363S variant (n = 4) and
nonrandomized assignment of glucocorticoid therapy in
an observational study. Basic in vitro and ex vivo studies
demonstrate that different sensitivity to glucocorticoids is
These findings support the possibility that glucocorticoid
sensitivity-modulated polymorphisms of GR may be impor-
tant in linking glucocorticoid excess in utero to cardio-
vascular and metabolic diseases in adulthood. Preterm and
SGA (birth weight less than 10th percentile for gestational
age) neonates usually undergo a period of accelerated
postnatal growth that enhances the risk of obesity and
elevated blood pressure later in life . In turn, for each
systolic and diastolic blood pressure at 7 years of age are
increased by 2.19 and 1.82, respectively . One potential
mechanism that may account for susceptibility to high blood
pressurein obese neonates may involve increased production
of angiotensinogen (AGT), a source for angiotensin (Ang) II
[135, 136]. It also appears that renal developmental pro-
gramming of hypertension may be sex dependent .
Testosterone tends to enhance the vasopressor arm while
estrogen enhances the vasodepressor arm. Only male rats
develop lower nephron numbers, higher blood pressure,
and lower GFR and proteinuria when exposed to Ang II
blockade or COX-2 inhibition during nephrogenesis [82,
89]. Early postnatal overfeeding induces early chronic renal
dysfunction in adult male, but not female rats . In sum-
mary, early postnatal factors may also program an increase
in later cardiovascular risk in both LBW and premature
infants. Therefore, it will be important to elucidate how to
optimize care in the setting of NICU to achieve optimal
kidney development in LBW or premature neonates after
International Journal of Nephrology9
3.8. Role of Epigenetic Factors in Kidney Development and
Programming of Renal Disease and Hypertension. Epigenetic
modifications provide one potential mechanism for how
environmental influences in early life cause long-term
changes in chronic disease susceptibility. The major players
in epigenetic mechanisms of gene expression regulation are
DNA or chromatin protein methylation, acetylation, and
chromatin remodeling. Posttranslational modifications of
histones such as histone acetylation and methylation of
affect chromatin function and alter gene expression in the
absence of changes in DNA sequence [138, 139]. It has been
shown that a maternal low-protein diet or tobacco use is
associated with reduced global methylation in the liver of the
exposure in utero [140, 141]. For example, maternal smoking
deregulates placental methylation of CpG dinucleotides,
which correlates with alterations in the expression of gene
pathways involved in regulation of cell death, morphology,
signaling, and metabolism . Since these gene pathways
are likely of biological and clinical significance, observed
alterations in gene methylation have the potential to impact
the health of the offspring.
Relevant to the regulation of normal and abnormal
kidney development, a recent study demonstrated a link
between Pax2, a transcription factor critical for renal mor-
phogenesis, and chromatin methylation . Pax 2 gene
encodes DNA-binding protein that can specify the interme-
diate mesoderm, a type of embryonic tissue that will subse-
quentlygeneratethe urogenital tract. The ubiquitous nuclear
4 (H3K4) methyltransferase complex that maintains active
chromatin domains by H3K4 methylation. Pax2 protein
promotes assembly of an H3K4 methyltransferase complex
through PTIP, thereby linking DNA-binding regulators of
deletion of PTIP in glomerular podocytes in mice led to
altered expression of select genes whose function may be
essential for podocyte foot process patterning, progressive
proteinuria, and podocyte ultrastructural defects similar to
chronic glomerular disease. These data demonstrate that
alterations or mutations in an epigenetic regulatory pathway
can alter the phenotypes of differentiated kidney cells and
lead to a chronic disease state .
Activation of p53, a tumor suppressor protein, results in
cell cycle arrest and apoptosis. Notably, tight regulation of
p53 activity is an absolute requirement for normal kidney
development . Altered methylation of the p53 gene has
been observed in the full-term IUGR rat kidney . Specif-
ically, IUGR increases p53 and Bax (proapoptotic gene) and
decreases Bcl-2 (anti-apoptotic gene) mRNA levels, leading
to enhanced renal apoptosis and reduced glomerular num-
ber. These changes are accompanied by decreased CpG
methylation of the renal p53 promoter. Thus, altered methy-
lation of p53 may represent a mechanism that contributes
to the fetal origins of adult kidney disease. An important
role for such an epigenetic mechanism as histone acetyla-
tion in programming of kidney disease is supported by
the observation that treatment of embryonic kidneys with
histone deacetylase inhibitors (HDACis) impairs the ureteric
bud branching morphogenesis program and provokes renal
growth arrest and apoptosis . In addition to DNA or
chromatin protein methylation or acetylation, gene expres-
sion may also be regulated at the posttranscriptional level
by noncoding microRNAs (miRNAs). miRNAs are small
endogenous RNA molecules about 22 nucleotides in length.
Dicer is an enzyme that cleaves precursor miRNAs into the
mature miRNAs. Silencing of target gene expression by miR-
NAs occurs by binding of the mature miRNA to the target
mRNA and preventing its translation or inducing its degra-
dation . The essential role for miRNAs in kidney
development is evident from the observation that targeted
genetic inactivation of Dicer in the UB in mice results in
hydronephrosis and renal cysts . These anomalies are
most likely due to loss of mature miRNAs in the ureteric bud
and its derivatives (renal pelvis, ureter, and collecting ducts),
leading to deregulated expression of genes that affect renal
collecting system development.
Whereas epigenetic dysregulation is increasingly impli-
cated in the regulation of normal kidney development, the
role of epigenetics in prenatal programming of such complex
diseases as hypertension remains largely uncharacterized.
Collecting duct epithelial sodium channel (ENaC) is critical
in Na+reabsorption in the distal tubule and hence the
regulation of extracellular fluid volume and blood pressure
. Activating ENaC mutations cause Liddle’s syndrome,
a hereditary disease characterized by hypertension .
Aldosterone, a major regulator of epithelial Na+absorption,
activates ENaC to increase extracellular fluid volume and
blood pressure. Recent studies reveal a novel role for epi-
genetic mechanisms in mediating aldosterone-induced con-
trol of ENaC gene expression. Aldosterone-induced H3K79
hypomethylation at specific subregions of ENaC alpha
promoter is associated with derepression of the ENaC alpha
promoter in murine inner medullary collecting ducts cells
. It is conceivable that hypomethylation of ENaC alpha
may lead to enhanced renal sodium reabsorption and thus
potentially elevated blood pressure in humans.
Promoter of a gene encoding for another solute carrier,
Na+-K+-2Cl−cotransporter 1 (NKCC1), normally expressed
in vascular smooth muscle cells, is also subject to epigenetic
regulation during postnatal development of hypertension
in spontaneously hypertensive rat (SHR) . Notably,
NKCC1 is implicated in the maintenance of vascular tone in
vivo since NKCC1-knockout mice have lower blood pressure
. In SHR, NKCC1 promoter is hypomethylated, and
expression of NKCC1 is increased after development of
hypertension compared to control Wistar-Kyoto rats (WKY)
. Thus, hypomethylation of NKCC1 plays an important
role in the upregulation of NKCC1 during development of
in the vasculature may underlie elevated blood pressure
. These data suggest a link between epigenetic modifi-
cation of genes and the resultant alteration in the expression
of genes in pathways associated with a range of physiologic
10International Journal of Nephrology
High blood pressure
Increased risk of
Increased risk of
Figure 1: Schematic representation of the proposed impact of adverse intrauterine environment on developmental programming of
hypertension and chronic kidney disease (CKD). Maternally mediated environmental modulation of renal gene expression in the offspring
leads to developmentally induced deviations from the optimal nephron number. A relative deficiency in the number of nephrons is thought
to create an increased risk of CKD, hypertension, and cardiovascular morbidity in later life. Epigenetic modifications not only change target
gene expression and program the phenotype of the developing fetus, but also account for transgenerational inheritance of programmed
phenotype via permanent epigenetic imprinting. UB: ureteric bud and M: metanephric mesenchyme.
Environmental influences during an individual’s early
life are not the sole cause of long-term changes in chronic
disease susceptibility. Emerging data suggest that integration
of signals from an individual’s mother’s lifetime nutritional
of environmental information. For example, offsprings of
LBW or preterm mothers are more likely to be born with
or preterm birth . Epigenetic imprinting, alteration of
gene expression based on their methylation status, is likely
to play a role in transmitting epigenetic information from
previous generations  (Figure 1).
4.Implicationsof the Stateof
Kidney inDevelopmental Originsof Disease
Preterm birth and LBW are risk factors for the development
of kidney disease and elevated blood pressure in later life.
Most studies seem to demonstrate that the association
between an adverse intrauterine environment and renal dis-
ease and hypertension in later life appears to be mediated, at
least in part, by impaired kidney development and nephron
endowment. Despite recent advances in elucidation of the
cellular and molecular mechanisms linking intrauterine
environment to kidney organogenesis and developmental
origins of disease, including hypertension and CKD, our
understanding of its cause in an individual patient is still
to be multifactorial and occur as a result of a combination
of epigenetic and environmental factors affecting genetically
susceptible individual. The best available surrogate markers
for low nephron number in children include LBW, IUGR,
short stature, and reduced kidney volume on ultrasound and
glomerulomegaly on kidney biopsy. Because morbidity in
perinatal programming may not manifest until later in life,
all patients who are at risk (eg., LBW and IUGR neonates)
should be closely followed throughout life. Medical moni-
toring of these neonates should include avoidance of neph-
rotoxic medications, optimization of nutrition, growth,
blood pressure, renal function, monitoring for proteinuria,
obesity counseling, and urinary tract imaging when indi-
cated. Gestational interventions should include optimization
of prenatal care and maternal nutrition, avoidance of medi-
opment (e.g., RAS blockers), maternal smoking, and alcohol
use. Introduction of more sensitive array-based methods
and recently developed epigenomic technologies, which
allow screening for multiple gene mutations and detection of
epigenetic modifications, may unravel a complex network
of molecular interactions. This will help to determine and
predict the occurrence and consequences of impaired neph-
rogenesis, CKD, and hypertension. Improved understanding
of epigenetic and other mechanisms of developmental pro-
gramming of CKD and hypertension will facilitate develop-
of these diseases in later life.
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