ABSTRACT Low birth weight (LBW) infants with reduced nephron numbers have significantly increased risk for hypertension later in life, which is a devastating health problem. The risk from a

reduction in nephron number alone is not clear. Recently, using conditional knock-out approach, we have developed a mutant mouse with reduced nephron number _in utero_ and no change in birth

weight, by deleting fibroblast growth factor receptor 2 (_fgfr2_) in the ureteric bud. Our purpose was to investigate the role of _in utero_ reduced nephron number alone in absence of LBW

as a risk for developing hypertension in adulthood. Using tail cuff blood pressure measurements we observed significant increases in systolic blood pressure in one year old mutant mice

observed increases in serum blood urea nitrogen (BUN) levels and histologic evidence of glomerular and renal tubular injury in mutant mice _versus_ controls. Thus, these studies suggest that

our mutant mice may serve as a relevant model to study the link between reduction of nephron number _in utero_ and the risk of hypertension and chronic renal failure in adulthood. SIMILAR

CONTENT BEING VIEWED BY OTHERS THE IMPACT OF INTRAUTERINE GROWTH RESTRICTION AND PREMATURITY ON NEPHRON ENDOWMENT Article 16 January 2023 QUANTIFIABLE AND REPRODUCIBLE PHENOTYPIC ASSESSMENT

OF A CONSTITUTIVE KNOCKOUT MOUSE MODEL FOR CONGENITAL NEPHROTIC SYNDROME OF THE FINNISH TYPE Article Open access 10 July 2024 KIDNEY VOLUME-TO-BIRTH WEIGHT RATIO AS AN ESTIMATE OF NEPHRON

ENDOWMENT IN EXTREMELY LOW BIRTH WEIGHT PRETERM INFANTS Article Open access 18 June 2024 MAIN Hypertension is a chronic disease with an incidence of more than 65 million people in the US

(1). According to recent estimates nearly one in three US adults have high blood pressure (1). This chronic and progressive disease is a leading cause of renal failure as well as increasing

risks of stroke, heart disease and blindness. Alarmingly, 7.8% of all infants born in the United States in 2002 had a LBW (<2500 g) (2); the majority of the LBW infants have low nephron

numbers and an increased risk of hypertension in adulthood (3,4). Recently a clinical study has reported finding elevated systolic blood pressure in adult women born preterm (5). In

addition, a meta-analysis that reviewed studies published between 1996 and 2000, concluded that birth weight was inversely related to systolic blood pressure (6). In 1988 Brenner _et al._

proposed that nephron number was inversely correlated to the risk of development of hypertension (7). Further evidence in support of this concept was recently documented in patients with a

history of primary hypertension or LV hypertrophy who had significantly increased heart weights but fewer glomeruli per kidney than matched normotensive controls (8). Most of the

experimental models to study the link between hypertension and reduced number of nephrons or LBW have used either unilateral nephrectomy models (9,10) or models with intrauterine growth

reduction (11–14). Although the collective data suggests a strong correlation with developing hypertension, the independent roles of LBW or reduced nephron numbers alone as important risk

factors in causing hypertension later in life are not clarified. One previously published report using glial cell line-derived neurotrophic factor (GDNF) heterozygous mice suggested a link

between _in utero_ reduction of nephron number alone and increased risk of hypertension (15). Recently, using a conditional knock out approach, we have developed a mutant mouse with reduced

nephron number _in utero_ and no change in birth weight, by deleting _fgfr2_ in the ureteric bud (16). The mice formed normal-appearing nephrons and appeared to have normal birth weights;

however, we observed a 24% decrease in nephron number in mutant mice both in embryonic explants and in 2 mo old adult mice _versus_ controls (14). This has given us a unique opportunity to

study the role of _in utero_ reduction of nephron number on progression of hypertension, changes in cardiac function, and changes in kidney function in the absence of LBW. The purpose of our

study was to further clarify the independent role of reduced nephron number on increased risk for hypertension in adulthood. In addition our study focused on an extensive investigation of

cardiac profiling including echocardiography and cardiac remodeling in this model. Finally we examined the effects of renal function in mutant _versus_ control mice MATERIALS AND METHODS

ANIMALS. All animal handling protocols were approved by Institutional Laboratory Animal Care and Use Committee at our institution. The generation of the conditional _fgfr2_ knock out mice

has been previously described (16). Briefly, mice with lox-p sites flanking critical regions of _fgfr2_ in the ureteric bud were bred with transgenic Hoxb7creEGFP (Hoxcre) mice to obtain

subsequent Hoxcre ± mice with deletion of _fgfr2_ from ureteric bud (mutants) and Hoxcre−/− mice (controls). Mutant (_n_ = 6) and littermate controls (_n_ = 8) were housed in a 12-h

light/dark facility with free access to food and water. All mice were fed Teklad Global 18% Protein Rodent Diet (Harlan Teklad, Madison, Wisconsin), which has 0.23% sodium content. The mice

were weighed at birth and then at one year of age with the genotypes blinded to investigator. Genotyping for cre and _fgfr2_ alleles were by PCR as previously described (16). The mice were

studied at approximately 1 y of age at which time the animals were anesthetized using 1% to 2% isoflurane, delivered by a small nose cone. BLOOD PRESSURE MEASUREMENTS. Following anesthetic

induction, a Harvard Tail BP monitor (Harvard Apparatus, Holliston, MA) was used to measure systolic blood pressures of both the mutant and control animals. All measurements were repeated

three times at 10 min intervals and performed at the same time of the day. ECHOCARDIOGRAPHY AND DOPPLER FLOW ANALYSIS. Cardiac performance was assessed by echocardiography as previously

described (17,18). Briefly, following anesthetic induction, mice were gently restrained in the left lateral decubitus position with elastic bands attached to a heated pad to maintain

normothermia. The chest area was shaved and ultrasound coupling gel was liberally applied to the left chest wall. Two dimensional and M-mode echocardiographic images were recorded and

analyzed by a Sonos 1000 echocardiograph and a 15 MHz pediatric ultrasonic probe (Hewlett-Packard Company, Andover, MA). Two-dimensional transverse LV imaging was used to position the probe

just distal to the mitral valve leaflets and M-mode images were then captured. Three loops of M-mode data were captured from each animal at approximately 5 min intervals and stored on a

digital disk until analyzed. Each of these captured image loops provided 7–12 heart cycles. Data were averaged from at least 5 cycles/loop. LV systolic (LVIDs) and diastolic (LVIDd) internal

dimensions were measured according to the American Society for Echocardiography leading-edge technique by a blinded investigator. These parameters allowed the determination of LV fractional

shortening (%FS), a measure of systolic function, by the equation: %FS = [(LVIDd-LVIDs)/ LVIDd]×100%. Ascending aortic flow velocity was determined using the ultrasonic probe in continuous

Doppler wave mode. The probe was maintained in the parasternal short axis orientation, but moved horizontally along the chest wall toward the suprasternal notch. While monitoring real time

color flow, the probe was slowly angled toward the head of the animal (probe face pointing toward the heart). This probe position provided color-enhanced definition of blood flow around the

aortic arch. The Doppler beam was centered on the ascending flow tract approximately 2 mm distal from the aortic valves and beat-to-beat cycles of aortic blood flow velocity were then

recorded in three captured loops as described above. From these recordings, peak aortic flow velocity and velocity-time integral (VTI) was determined for at least 5 beats/loop for each

animal. After sacrifice, aortic root cross-sectional area was measured, and cardiac output (CO) was calculated by the equation: CO = heart rate × VTI × aortic cross-sectional area.

HISTOCHEMISTRY AND DIGITAL IMAGE ANALYSIS. Animals were killed with 100 mg/kg, intra peritoneal, pentobarbital sodium (Abbott Laboratories, Chicago, IL). The apical portion of the heart was

bisected just distal to the mitral valve and immersed in 10% formalin. Kidneys were weighed and then bisected through the hilum in the transverse plane. Following a 48-h fixation period in

10% buffered formalin, tissues were dehydrated and paraffin-embedded using standard procedures, as previously described (17). Serial 5-μm tissue sections were placed on microscope slides,

dewaxed, and rehydrated for routine histochemical staining (hematoxylin & eosin) for morphologic studies. Photomicrographs were captured on a Polaroid DMC high-resolution digital camera,

mounted on an Olympus research microscope (Pixera Inc., Houston, TX). The images were analyzed with Image Pro 5.0 image analysis software (Media Cybernetics, Silver Spring, MD). Hematoxylin

and eosin stained slides were used to determine LV wall thickness (at the equatorial midline). Each heart cross-section was captured in its entirety at 2.5× magnification and internal and

external edges were traced (automated edge detection, Image Pro 5.0) for the left ventricle to determine the LV wall thickness. For all parameters measured, intra- and inter observer

variabilities were less than 5% (coefficients of variation for three daily measurements made by three different investigators evaluating three hearts). RENAL PROFILING. Before sacrifice, 24

h urine samples were obtained for measurement of urine chemistries and blood samples were collected by cardiac puncture, at the time of sacrifice, to measure serum chemistries (electrolytes,

creatinine, BUN, potassium, bicarbonate calcium, osmolality). Serum and urine urea and creatinine levels were measured using a VITROS apparatus (Ortho-Clinical diagnostics, Rochester, NY)

at the animal Morphology Core (Ohio State University, Columbus, OH). Serum and urine electrolytes were analyzed by a Hitachi 911 apparatus (Roche, Indianapolis, IN) at the animal Morphology

Core. Heart tissue was weighed and rapidly isolated for histology and/or snap frozen for biochemical analysis. STATISTICS. All statistical evaluations were performed using SigmaStat

statistical software (Jandel Scientific, San Rafael, CA). Statistical comparisons were determined using _t_ test. In all tests _p_ < 0.05 were considered significant. RESULTS BODY WEIGHTS

IN MUTANT VERSUS CONTROL MICE. We detected no statistically significant changes in the body weights of the newborn mutant mice compared with controls (1.43 ± 0.09 _versus_ 1.50 ± 0.07 g,

_p_ = 0.6). Similarly, we observed no statistically significant changes in the body weights of the adult (1-y-old) (34.4 ± 1.9 _versus_ 35.6 ± 1.4 g, _p_ = 0.42) mutant mice _versus_

controls. BLOOD PRESSURE PROFILING AND CARDIAC REMODELING IN ADULT MUTANT MICE. We detected striking increases in systolic blood pressures in adult mutant mice _versus_ control littermates

(133 ± 7 _versus_ 113 ± 3 mm Hg, _p_ = 0.001), as shown in Fig. 1. To determine whether the mutants developed end organ damage from increased blood pressures we examined the mutants for

cardiac remodeling. Representative photomicrographs (2.5× magnification) of heart cross-sections through equatorial midline reveal significant increases in overall mutant left ventricle size

as compared with controls (Fig. 2_A,B_). Quantitatively, heart weights normalized to body weights were significantly increased in mutants _versus_ controls (0.004 ± 0.002 _versus_ 0.0056 ±

0.004 g/g, _p_ < 0.05) (Fig. 2_C_). In addition, overall LV area (area between outer and inner lines in Fig. 2_A_, 2_B_) was significantly increased in mutants _versus_ controls (Fig.

2_D_). Finally average LV wall thickness calculated by digital image analysis software, which traced the outer and inner edges of the left ventricle (Fig. E2) was dramatically increased in

mutant _versus_ control mice (0.78 ± 0.09 _versus_ 0.55 ± 0.058 mm, _p_ < 0.05). Thus hypertension, as demonstrated by increased blood pressure and cardiac remodeling was clearly present

in the mutant mice. CARDIAC PROFILING. Representative two-dimensional M-mode tracings of systole-diastole cycles from a control and mutant animal are shown in Fig. 3_A_ (top panel). The

waveforms from control and mutant animals were not different, consistent with no alterations in the fractional shortening (49.8 ± 2.2 _versus_ 49.1 ± 2.47%, _p_ = 0.84). Resting heart rate

(440 ± 23.6 _versus_ 500 ± 18.9 bpm, _p_ = 0.07) was not different between the groups. Although there was a trend for decreased cardiac output (14.67 ± 2.02 _versus_ 19.78 ± 1.5 mL/min, _p_

= 0.06) and increased stroke volume (33.85 ± 4.67 _versus_ 39.38 ± 2.08 μL, _p_ = 0.26) in mutant mice _versus_ controls, we observed no significant changes in either parameter. Systemic

vascular resistance was dramatically increased in mutant mice _versus_ controls (11.31 ± 3.1 _versus_ 6.13 ± 0.38 mm Hg × min/mL, _p_ < 0.05) (Fig. 3_B_). Thus there are no differences in

cardiac output but significant increases in systemic vascular resistance in mutant mice _versus_ controls. RENAL PROFILING. We observed significant increases in serum BUN levels (37.2 ± 7.6

_versus_ 22.8 ± 3.8 mg/dL, _p_ < 0.05) in mutant mice compared with controls, shown in Fig. 4_A_. While there was an increasing trend in mutant serum creatinine levels (0.36 ± 0.2

_versus_ 0.30 ± 0.01 mg/dL, _p_ = 0.17) and creatinine clearance (0.099 ± 0.01 _versus_ 0.138 ± 0.02 mL/min, _p_ = 0.09), we detected no significant changes in mutant mice _versus_ controls

(Fig. 4_B_ and not shown). We detected no changes in the fractional excretion of sodium (0.0056 ± 0.002 _versus_ 0.0048 ± 0.002%, _p_ = 0.4) in the mutant mice _versus_ controls. Comparing

controls with mutants, we observed no statistically significant changes in serum sodium (153 ± 1 _versus_ 154 ± 1 mEq/L), potassium (7.5 ± 0.2 _versus_ 7.8 ± 0.3 mEq/L), chloride (113 ± 1

_versus_ 114 ± 1 mEq/L), bicarbonate (28 ± 1 _versus_ 26 ± 1 mM), or calcium (11 ± 0.2 _versus_ 11 ± 0.1 mEq/L). Likewise, in comparing controls with mutants we observed no statistically

significant changes in 24 h urine sodium (49 ± 7 _versus_ 33 ± 5 mEq/L), calcium (5 ± 0.3 _versus_ 4 ± 1.0 mEq/L), creatinine (22.8 ± 3.2 _versus_ 14.7 ± 3.4 mg/dL), or Osmols (590 ± 85

_versus_ 476 ± 88 mosmol/kg). In comparing the kidneys at the time of sacrifice, we noted that one mutant mouse developed unilateral hydronephrosis, while the all other mutant and controls

appeared grossly normal (data not shown). Mean kidney weights between the controls (n = 16) (0.21 ± 0.02 g) and mutants (n = 12) (0.26 ± 0.1 g) were not significantly different. Even when

removing the single hydronephrotic kidney weight from the calculation, the mutant mean kidney weight (n = 11) (0.18 ± 0.03 g) was still not significantly different from the control mean

weight. We also performed H & E staining on paraffin kidney sections from both the mutants and controls. In comparison with the controls, the hydronephrotic mutant kidney demonstrated

marked parenchymal atrophy (data not shown). In addition, the non-hydronephrotic mutant kidneys demonstrated proteinaceous renal casts in cortical and medullary tubules and regenerative

tubules with cytoplasmic basophilia (Fig. 5_B_). Mutant glomeruli demonstrated nuclear crowding, thickening and hypercellularity of the glomerular tuft, dilatation of Bowman's space,

and thickening of Bowman's capsule (Fig. 5_D_). Thus the mutant kidneys had histologic evidence of chronic renal disease that correlated with the increases in BUN relative to controls.

DISCUSSION LBW infants with reduced nephron numbers have a significantly increased risk for hypertension later in life, which is a significant health problem (4–6). While the reason(s) for

the increased risk is not clear, reduction in nephron number and LBW have each been implicated (4–6). Optimal therapies for this condition are poorly defined and, as the incidence continues

to rise, the importance and medical costs associated with this syndrome are likely to escalate. In 1988, Brenner _et al._ proposed that reduced nephron number or “nephron underdosing”

independently and inversely correlated to risk of developing hypertension in adulthood (7). While some recent clinical data supports this hypothesis, there is no clear consensus regarding

the association between reduced nephron number and development of hypertension. Most of the experimental data employs unilateral nephrectomy models (_e.g._ sheep) to study the underlying

mechanisms of hypertension (9–10). However, increasing evidence suggests that hypertension, although developed in adulthood are primed in fetal life (4) and therefore experimental models

identifying the phenomenon _in utero_ would greatly influence our understanding of the patho-physiologic mechanisms associated with the disease. Here we pursued the development of a relevant

and convenient _in utero_ mouse model with reduced nephron numbers. The data presented herein provide evidence that the mutant mouse model we used is an excellent model to study effects of

_in utero_ reduced nephron number alone on development of hypertension in adulthood and are consistent with observations in clinical settings. Our data showing a link between a reduction of

nephron number _in utero_ and hypertension in adulthood is consistent with data in GDNF heterozygous mice (15). These mice experience a 30% reduction in nephron number during fetal life,

which results in significant elevations in blood pressure at 14 mo of age. Although birth weights were not recorded, it was implied that there were no differences between mutants and

controls. In our model, there is a 24% reduction in nephron number due to lower ureteric bud tips numbers, and despite no differences in birth weight, mutants have dramatic increases in

blood pressure at one year of age. In our study, the increases in blood pressure were accompanied by significant cardiac remodeling. Overall heart mass/body mass, LV area, and LV

wall-thickness were all increased in our mutant mice relative to controls, clearly indicating end-organ injury from hypertension. It is possible that the mutant mice in our study are

hypertensive for some reason other than a reduction in nephron number. However, 2 independent mouse models (our mice and the GDNF heterozygotes) both develop a bilateral, symmetric reduction

in nephron number and subsequent hypertension, strongly supporting that alteration in nephron number alone increases the risk of hypertension later in life. Since hypertension must be

associated with changes in cardiac output and/or systemic vascular resistance, we performed 2-dimensional echocardiography to clarify the changes in our model. We observed significant

increases in systemic vascular resistance and a decreasing trend in cardiac output. In contrast, Mortiz _et al._ have associated increased blood pressure to increased cardiac output in sheep

models of unilateral nephrectomy (10). One potential reason for the discrepancy between the studies may be related the timing of the data collection. A commonly accepted paradigm for

primary hypertension is that early on, there is an increase in cardiac output and a normal total peripheral resistance, followed by adaptive changes causing and eventual reduction in cardiac

output and increased total peripheral resistance (19). The differences may also be species dependent (sheep _versus_ mice). Finally, while the sheep model is a unilateral nephrectomy model,

the mice in this study never form the full complement of nephrons. In addition to the changes in blood pressure, we observed significant increases in BUN levels in our mutant mice compared

with controls. In contrast, there were no statistically significant differences in mutant creatinine levels _versus_ controls. One potential explanation is that the mice had decreased

effective intravascular volume (_e.g._ dehydration), which is often known to cause a disproportionate increase in BUN relative to creatinine (20). This is not likely given that adult mutant

weights and fractional excretion of sodium measurements were not lower than controls (as would be expected with dehydration or intravascular volume depletion). The mutant mice more likely

have mild intrinsic renal dysfunction as is strongly supported by the histologic evidence of glomerular and tubular injury in these mice. Although one would then expect increases in serum

creatinine in mutants _versus_ controls (as well as the increases in BUN), it may be that the intrinsic lab error in our creatinine measurements does not allow us to measure these

differences. In summary, we have shown that adult _fgfr2_ ureteric bud knock out mutant mice develop hypertension and we have established its role as a relevant _in utero_ mouse model to

study hypertension and chronic renal failure that develops in adult life. Further studies defining the link between adult hypertension, chronic renal failure, and prenatal loss of nephrons

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would like to thank Dr. Michael Robinson, Dr. Kirk McHugh, and Dr. Donna Kusewitt for helpful discussions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Centers for Cell and Vascular

Biology, Columbus Children's Research Institute, Columbus, 43205, OH Deepali Pitre Poladia, Kayle Kish, Benjamin Kutay & Carlton M Bates * Cardiovascular Medicine, Columbus

Children's Research Institute, Columbus, 43205, OH John Bauer * Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, 75235, TX Michel Baum * Department of

Pediatrics, The Ohio State University College of Medicine and Public Health, Columbus, 43210, OH Carlton M Bates Authors * Deepali Pitre Poladia View author publications You can also search

for this author inPubMed Google Scholar * Kayle Kish View author publications You can also search for this author inPubMed Google Scholar * Benjamin Kutay View author publications You can

also search for this author inPubMed Google Scholar * John Bauer View author publications You can also search for this author inPubMed Google Scholar * Michel Baum View author publications

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Correspondence to Carlton M Bates. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Poladia, D., Kish, K., Kutay, B. _et al._ Link Between Reduced Nephron

Number and Hypertension: Studies in a Mutant Mouse Model. _Pediatr Res_ 59, 489–493 (2006). https://doi.org/10.1203/01.pdr.0000202764.02295.45 Download citation * Received: 02 August 2005 *

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