Nephron Number Research Articles

Renal outcome in children born preterm with neonatal acute renal failure: IRENEO-a prospective controlled study.

Acute kidney injury (AKI) is a severe complication of prematurity, with currently unknown consequences for renal function in childhood. The objective of this study was to search for signs of reduced nephron number in children aged 3-10years who had been born preterm with neonatal AKI and compare this group to control children. IRENEO was a prospective, controlled study conducted in 2013 in Nantes University Hospital. Children who were born at less than 33weeks gestational age (GA) and included in the LIFT cohort were eligible for entry. Twenty-five children with AKI (AKI-C) and 49 no-AKI children were matched on a propensity score of neonatal AKI and age. AKI was defined as a serum creatinine level higher than critical values: 1.6mg/dl (GA 24-27 weeks), 1.1mg/dl (28-29) and 1mg/dl (GA 30-32). Renal function was evaluated during childhood. Mean age of the children at the time of the study was 6.6years. No difference in microalbuminuria, estimated glomerular filtration rate (GFR) or pulse wave velocity was observed between the two groups. Renal volume was lower in the AKI-C group (57 vs. 68; p = 0.04). In the entire cohort, 10.8% had a microalbuminuria, and 23% had a diminished GFR (median 79ml/min/1.73m2). The GFR was lower in children with very low birth weight of <1000g (99 vs. 107ml/min/1.73m2; p = 0.04). In children born preterm, neonatal AKI does not seem to influence renal function. However, independent ofAKI, a large proportion of very preterm infants, especially those with very low birth weight, presented with signs of nephron reduction, thus requiring follow-up with a nephrologist.

Interplay between chronic kidney disease (CKD) and upper tract urothelial carcinomas (UUC): foe or friend?

Although upper tract urothelial carcinomas (UUC) is curable through nephrectomy or nephroureterectomy, progression of chronic kidney disease (CKD) and CKD-related mortality have been highlighted as clinical challenges in recent years owing to the loss of a large number of nephrons. While CKD can promote the development of UUC, other risk factors such as hypertension, diabetes mellitus, advanced age, and anemia can facilitate the progression of CKD. Conversely, CKD is especially prevalent in UUC patients. However, the relationship between CKD and UUC, mechanisms for CKD causing UUC, and gender disparity of UUC of CKD patients have so far not been well-reviewed. As UUC gradually grows, the cancer can be a physical obstacle in the urinary tract. It will cause an increased tract pressure, subsequently resulting in the dysfunction of both nephrons and kidney. At the molecular level, reduced level of oxidative stress was observed in female UUC patients. Furthermore, radical nephrectomy therapy for UUC patients accelerates the progress of chronic kidney dysfunction. Incidentally, the remedies for CKD containing aristolochic acid (AA) are carcinogenic. Our present review offers a comprehensive look at the relationship between CKD and UUC from multiple perspectives. Early and precise identification of progression of CKD and UUC will benefit the patients at high-risk of CKD or UUC, which will also be instructive in directing timely and effective therapeutic interventions whenever necessary. It may also shed light on unveiling the underlying mechanisms of carcinogenesis of UUC, preventing CKD progression, and prolonging the patients' overall survival.

Development: Unique genetic determinants of human kidney development.

Human kidneys have many features in common with those of other species, but also unique properties. A detailed human–mouse comparison of the genetic programme governing early events in nephron formation has revealed interspecies differences that could explain how nephron number in adult kidneys is determined.

The impact of hypoxia on nephrogenesis.

Kidney development depends on outgrowth of the ureteric bud into the metanephric mesenchyme. The number of ureteric bud branching events determines the final number of nephrons, which correlates inversely with the risk for development of chronic kidney disease and arterial hypertension during lifetime. The purpose of this review is to highlight the influence of oxygen on nephrogenesis and to describe cellular mechanisms by which hypoxia can impair nephron formation. Although kidney development normally takes place under hypoxic conditions, nephrogenesis is impaired when oxygen availability falls below the usual range. Hypoxia-inducible factors (HIF) play an important role in linking low oxygen concentrations to the biology of nephron formation, but their effect appears to be cell type dependent. In ureteric bud cells, HIF stimulates tubulogenesis, whereas HIF stabilization in cells of the metanephric mesenchyme results in secretion of growth factors, including vascular endothelial growth factor A, which in aggregate inhibit ureteric bud branching. The balance between pro and antibranching effects may be altered in various ways, but the inhibitory effect usually seems to predominate under reduced oxygen concentrations, explaining how intrauterine hypoxia can lead to low nephron numbers. Oxygen availability has a complex influence on nephrogenesis. Oxygen concentrations outside an optimal low range may affect nephron endowment. Associations between placental insufficiency and increased risk for chronic kidney disease and arterial hypertension during later life may to a large extent be due to direct effects of reduced oxygen supply to the metanephric mesenchyme and mediated through the HIF pathway.

Maternal corticosterone exposure in the mouse programs sex-specific renal adaptations in the renin-angiotensin-aldosterone system in 6-month offspring.

Short‐term maternal corticosterone (Cort) administration at mid‐gestation in the mouse reduces nephron number in both sexes while programming renal and cardiovascular dysfunction in 12‐month male but not female offspring. The renal renin–angiotensin–aldosterone system (RAAS), functions in a sexually dimorphic manner to regulate both renal and cardiovascular physiology. This study aimed to identify if there are sex‐specific differences in basal levels of the intrarenal RAAS and to determine the impact of maternal Cort exposure on the RAAS in male and female offspring at 6 months of age. While intrarenal renin concentrations were higher in untreated females compared to untreated males, renal angiotensin II concentrations were higher in males than females. Furthermore, basal plasma aldosterone concentrations were greater in females than males. Cort exposed male but not female offspring had reduced water intake and urine excretion. Cort exposure increased renal renin concentrations and elevated mRNA expression of Ren1, Ace2, and Mas1 in male but not female offspring. In addition, male Cort exposed offspring had increased expression of the aldosterone receptor, Nr3c2 and renal sodium transporters. In contrast, Cort exposure increased Agtr1a mRNA levels in female offspring only. This study demonstrates that maternal Cort exposure alters key regulators of renal function in a sex‐specific manner at 6 months of life. These finding likely contribute to the disease outcomes in male but not female offspring in later life and highlights the importance of renal factors other than nephron number in the programming of renal and cardiovascular disease.

Perinatal programming of renal function.

Perinatal programming of renal function reflects the epigenetic alteration of genetically determined development by environmental factors. These include intrauterine malnutrition, pre and postnatal overnutrition, glucocorticoids, and certain toxins such as smoking. This review aims to summarize the most important findings. Human studies may show an increased susceptibility toward the general prevalence of renal failure in already small for gestational age children and adolescents. In particular, glomerular diseases present with a more severe clinical course. Partially related, partially independently, arterial hypertension is found in this at-risk group. The findings can mostly be confirmed in animal models. Both intrauterine nutrient deprived and overfed rodents show a tendency toward developing glomerulosclerosis and other renal disorders. Animal studies attempt to imitate clinical conditions, however, there are difficulties in transferring the findings to the human setting. The reduction of nephron number, especially in intrauterine growth-restricted humans and animals, is one mechanism of perinatal programming in the kidneys. In addition, vascular and endocrine alterations are prevalent. The molecular changes behind these mechanisms include epigenetic changes such as DNA-methylation, microRNAs, and histone modifications. Future research will have to establish clinical studies with clear and well defined inclusion criteria which also reflect prenatal life. The use of transgenic animal models might help to obtain a deeper insight into the underlying mechanisms.

Maternal hypomagnesemia alters renal function but does not program changes in the cardiovascular physiology of adult offspring.

Maternal undernutrition is known to adversely impact fetal health and development. Insults experienced in utero alter development of the fetus as it adapts to microenvironment stressors, leading to growth restriction and subsequent low birth weight. Infants born small for gestational age have significantly increased risk of developing cardiovascular and renal disease in later life, an effect that is often characterized by hypertension and reduced glomerular number. Maternal magnesium (Mg2+) deficiency during pregnancy impairs fetal growth, however, the long-term health consequences for the offspring remain unknown. Here, we used a mouse model of dietary Mg2+ deficiency before and during pregnancy to investigate cardiovascular and renal outcomes in male and female adult offspring at 6 months of age. There were no differences between groups in 24-h mean arterial pressure or heart rate as measured by radiotelemetry. Cardiovascular responses to aversive (restraint, dirty cage switch) and non-aversive (feeding response) stressors were also similar in all groups. There were no differences in nephron number, however, Mg2+-deficient offspring had increased urine flow (in both males and females) and reduced Mg2+ excretion (in males only). Despite evidence suggesting that maternal nutrient restriction programs for hypertension in adult offspring, we found that a moderate level of maternal dietary Mg2+ deficiency did not program for a nephron deficit, or alter cardiovascular function at 6 months of age. These data suggest there are no long-term adverse outcomes for the cardiovascular health of offspring of Mg2+ deficient mothers.

Indirect estimation of nephron number: a new tool to predict outcomes in renal transplantation?

Indirect estimation of nephron number: a new tool to predict outcomes in renal transplantation?

Long-term impact of unilateral hypo/dysplastic kidney in infants with primary vesicoureteral reflux

Renal abnormality is not a rare finding in infants with primary VUR. The pathophysiology of the renal abnormality is considered to be congenital or acquired. Congenital hypo/dysplastic kidney is a common finding in infants with primary VUR, especially in boys. However, the long-term impact of unilateral hypo/dysplastic kidney has not been elucidated. The aim of the current study is to clarify the long-term impact of unilateral hypo/dysplastic kidney with primary vesicoureteral reflux diagnosed in infancy. The medical records of patients with primary VUR detected in infancy with unilateral hypo/dysplastic kidney on initial nuclear renal scan (<40% relative renal function) and no scar on the contralateral kidney were reviewed retrospectively. Among them, 29 patients who were followed for more than 5 years were included in this study. Their clinical outcomes including chronic kidney disease (CKD) stage using estimated glomerular filtration rate (GFR) and the incidences of hypertension and proteinuria were analyzed. Mean age at final visit was 12.4 years (range 5.9-22.2). Estimated GFR was evaluated in 26 patients at a mean age of 12.0 years (5.9-22.2). CKD stage was 1 in all. According to the guidelines of the Japanese Society of Hypertension, while none exceeded the standard level of systolic blood pressure (BP), two patients slightly exceeded the standard level of diastolic BP. In addition, no significant proteinuria was detected in all patients, although microalbuminemia was detected in 7.7% of patients. The prognosis of reflux nephropathy depends on the remnant renal tissue mass, that is, the number of normal nephrons. The normal congenital solitary kidney is reported to be hyperplastic with normal-sized glomeruli rather than hypertrophic ones with larger nephrons, and to have better long-term outcome regarding renal function. Accordingly, we speculated that patients with unilateral hypo/dysplastic kidney would have a similar number of nephrons to those without hypo/dysplastic kidney who have no or minimal scar as far as the contralateral kidney is well preserved. Long-term outcome of the current retrospective study was consistent with our speculation in terms of estimated GFR, proteinuria, or hypertension. The present study demonstrated that significant clinical findings related to unilateral hypo/dysplastic kidney detected in infancy were rarely observed in the long term. Accordingly, unilateral hypo/dysplastic kidney seems to be a benign condition. To confirm this finding, further follow-up of these patients is necessary.

Ret and Etv4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis.

Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM), combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret−/− or Etv4−/− sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret/Etv4 signaling promotes directed cell movements in the ureteric bud tips, and suggest a model in which these cell movements mediate branching morphogenesis.

Estimated nephron number of the remaining donor kidney: impact on living kidney donor outcomes.

It has been demonstrated that low birth weight gives rise to a reduction in nephron number with increased risks for hypertension and renal disease. Its impact on renal function in kidney donors, however, has not been addressed. To investigate the impact of birth weight, kidney weight, kidney volume and estimated nephron number on kidney function, we collected data from 91 living kidney donors before nephrectomy, at +12, +36 and +60 months after nephrectomy. Birth weight showed a positive correlation with estimated glomerular filtration rate (eGFR) at +12, +36 and +60 months after nephrectomy (P < 0.05). The strongest link was observed in donors >50 years old (R = 0.535, P < 0.001 at +12 months). Estimated nephron number and eGFR showed a strong positive correlation at +12, +36 and +60 months after nephrectomy (R = 0.540; R = 0.459; R = 0.506, P < 0.05). Daily proteinuria at +12 months showed a negative correlation with birth weight (P = 0.009). Donors with new-onset hypertension showed significantly lower birth weights and higher uric acid levels (P < 0.05). Kidney weight and volume did not show any impact on donor outcomes (P > 0.05). Low nephron number predisposes donors to inferior remaining eGFR, hypertension and proteinuria. The strong correlation in elderly donors may be attributed to reduced renal functional reserve due to the decline of renal function with age.

Maternal protein restriction reduces perlecan at mid-metanephrogenesis in rats.

Maternal dietary protein restriction reduces nephron number in offspring and increases the risk of cardiovascular and chronic kidney diseases. Perlecan is the major basement membrane/extracellular matrix heparan sulfate proteoglycan (HSPG) that plays a crucial role in nephron formation. This study was to determine whether maternal dietary protein restriction during pregnancy leads to an abnormal perlecan expression pattern during kidney development and a correlation with aberrant cell proliferation and apoptosis. Pregnant Sprague-Dawley rats were divided into two groups, maintained on either a low-protein diet (MLP group) or a normal-protein diet (MNP group). Kidneys were dissected from embryos of different kidney development stages. Real-time PCR and immunohistochemistry were performed to detect the transcript level of rHSPG2, the coding gene of perlecan, and its protein expression pattern. Apoptosis and proliferation cell were detected by TUNEL system and Ki67 marker. Embryonic weights and nephron number were significantly affected by maternal low protein diets. The transcript level of rHSPG2 in the MLP group was significantly lower at embryonic day 18 and the neonatal period. Immunohistochemistry study was consistent with the RT-PCR results. The proliferation level of the MLP group was significantly lower than the MNP group at E18 and more apoptotic cells was detected in MLP newborn. Maternal protein restriction reduced the expression of perlecan and lead aberrant cell proliferation and apoptosis during mid-metanephrogenesis in offspring. This data may provide new evidence to understand the mechanism of reduced nephron number due to maternal protein restriction and enlighten solution.

Roles and regulation of bone morphogenetic protein-7 in kidney development and diseases

The gene encoding bone morphogenetic protein-7 (Bmp7) is expressed in the developing kidney in embryos and also in the mature organ in adults. During kidney development, expression of Bmp7 is essential to determine the final number of nephrons in and proper size of the organ. The secreted BMP7 acts on the nephron progenitor cells to exert its dual functions: To maintain and expand the progenitor population and to provide them with competence to respond to differentiation cues, each relying on distinct signaling pathways. Intriguingly, in the adult organ, BMP7 has been implicated in protection against and regeneration from injury. Exogenous administration of recombinant BMP7 to animal models of kidney diseases has shown promising effects in counteracting inflammation, apoptosis and fibrosis evoked upon injury. Although the expression pattern of Bmp7 has been well described, the mechanisms by which it is regulated have remained elusive and the processes by which the secretion sites of BMP7 impinge upon its functions in kidney development and diseases have not yet been assessed. Understanding the regulatory mechanisms will pave the way towards gaining better insight into the roles of BMP7, and to achieving desired control of the gene expression as a therapeutic strategy for kidney diseases.

Genetic low nephron number hypertension is associated with altered expression of key components of the renin-angiotensin system during nephrogenesis.

This study investigates key components of the renin-angiotensin system (RAS) which play a central role in nephrogenesis and possibly in fetal programming of arterial hypertension in adult life. We compared a genetic rat model with inborn nephron deficit, the Munich Wistar Fromter rat (MWF), to normotensive Wistar rats during nephrogenesis at day 19 of fetal development (E19) and at postnatal day 7 (D7). At E19 renal mRNA of angiotensin II type 1a (AT1a) (-50%, P<0.05) and type 1b (AT1b) (-55%, P<0.05) receptors were significantly decreased and renal mRNA expression of angiotensin II type 2 (AT2) receptor was fivefold increased in MWF (n=8) as compared to Wistar rats (n=8). At D7 renal mRNA expression of AT1a (-42%, P<0.05) remained lower in MWF (n=8) as compared to Wistar (n=7). Renal mRNA expression of AT2 (-30%, P>0.05) decreased in MWF (n=8) to about the level of the Wistar control (n=6). Altered fetal expression of key molecules of the renin-angiotensin system in MWF indicates a possible role in genetic low nephron number hypertension.

Prognostic factors and biomarkers of congenital obstructive nephropathy.

Congenital obstructive nephropathy (CON) is the leading cause of chronic kidney disease (CKD) in children. Anomalies of the urinary tract are often associated with abnormal nephrogenesis, which is compounded by obstructive injury and by maternal risk factors associated with low birth weight. Currently available fetal and postnatal imaging and analytes of amniotic fluid, urine, or blood lack predictive value. For ureteropelvic junction obstruction, biomarkers are needed for optimal timing of pyeloplasty; for posterior urethral valves, biomarkers of long-term prognosis and CKD are needed. The initial nephron number may be a major determinant of progression of CKD, and most patients with CON who progress to renal failure reach this point in adulthood, presumably compounded by episodes of acute kidney injury. Biomarkers of tubular injury may be of particular value in predicting the need for surgical intervention or in tracking progression of CKD, and must be adjusted for patient age. Discovery of new biomarkers may depend on "unbiased" proteomics, whereby patterns of urinary peptide fragments from patients with CON are analyzed in comparison to controls. Most promising are the analysis of urinary exosomes (restricting biomarkers to relevant tubular cells) and quantitative magnetic resonance imaging techniques allowing precise determination of nephron number and tubular mass. The greatest need is for large prospective multicenter studies with centralized biomarker sample repositories to follow patients with CON from fetal life through adulthood.

The role of maternal nutrition, metabolic function and the placenta in developmental programming of renal dysfunction.

The intrauterine environment is critical for the development of the foetus. Barker and colleagues were the first to identify that adverse perturbations during foetal development are associated with an increased risk of developing diseases in adulthood, including cardiorenal disease. Specifically for the kidney, perturbations in utero can lead to nephron deficits and renal dysfunction by a number of mechanisms. Altered programming of nephron number is associated with an increased risk of developing kidney disease via glomerular hypertrophy and reduced vasodilative capacity of the renal blood vessels; both of which would contribute to hypertension in adulthood, with males being more susceptible to disease outcomes. Additionally, alterations in the renin-angiotensin system (RAS) such as an upregulation or downregulation of specific receptors, depending on the nature of the insult, have also been implicated in the development of renal dysfunction. Sex-specific differences in the expression of the RAS during late gestation and in the early postnatal environment have also been identified. Extensive research has demonstrated that both uteroplacental insufficiency and maternal malnutrition alter renal development in utero. Equally, exposure to maternal diabetes and maternal obesity during development are also associated with an increased risk of developing renal disease, however, the mechanism behind this association is poorly understood. Therefore, identifying the link between an adverse intrauterine environment and the programmed kidney disease risk in adulthood may facilitate the development of strategies to alleviate the epidemics of cardiorenal disease worldwide, in addition to understanding why males are more susceptible to adult-onset cardiovascular diseases.

Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis

Reduced nephron number predisposes to hypertension and kidney disease. Interaction of the branching ureteric bud and surrounding mesenchymal cells determines nephron number. Since oxygen supply may be critical for intrauterine development, we tested whether hypoxia and hypoxia-inducible factor-1α (HIF-1α) influence nephrogenesis. We found that HIF-1α is required for branching of MDCK cells. In addition, culture of metanephric mouse kidneys with ureteric bud cell-specific stabilization or knockout of HIF-1α revealed a positive impact of HIF-1α on nephrogenesis. In contrast, widespread stabilization of HIF-1α in metanephric kidneys through hypoxia or HIF stabilizers impaired nephrogenesis, and pharmacological HIF inhibition enhanced nephrogenesis. Several lines of evidence suggest an inhibitory effect through the hypoxia response of mesenchymal cells. HIF-1α was expressed in mesenchymal cells during nephrogenesis. Expression of the anti-branching factors Bmp4 and Vegfa, secreted by mesenchymal cells, was increased upon HIF stabilization. The conditioned medium from hypoxic metanephric kidneys inhibited MDCK branching, which was partially rescued by Vegfa antibodies. Thus, the effect of HIF-1α on nephrogenesis appears context dependent. While HIF-1α in the ureteric bud is of importance for proper branching morphogenesis, the net effect of hypoxia-induced HIF activation in the embryonic kidney appears to be mesenchymal cell-dependent inhibition of ureter branching.

Urogenital development in Pallister-Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor.

Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.

Ouabain rescues rat nephrogenesis during intrauterine growth restriction by regulating the complement and coagulation cascades and calcium signaling pathway.

Intrauterine growth restriction (IUGR) is associated with a reduction in the numbers of nephrons in neonates, which increases the risk of hypertension. Our previous study showed that ouabain protects the development of the embryonic kidney during IUGR. To explore this molecular mechanism, IUGR rats were induced by protein and calorie restriction throughout pregnancy, and ouabain was delivered using a mini osmotic pump. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) of the embryonic kidneys. DEGs were submitted to the Database for Annotation and Visualization and Integrated Discovery, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Maternal malnutrition significantly reduced fetal weight, but ouabain treatment had no significant effect on body weight. A total of 322 (177 upregulated and 145 downregulated) DEGs were detected between control and the IUGR group. Meanwhile, 318 DEGs were found to be differentially expressed (180 increased and 138 decreased) between the IUGR group and the ouabain-treated group. KEGG pathway analysis indicated that maternal undernutrition mainly disrupts the complement and coagulation cascades and the calcium signaling pathway, which could be protected by ouabain treatment. Taken together, these two biological pathways may play an important role in nephrogenesis, indicating potential novel therapeutic targets against the unfavorable effects of IUGR.

The placenta is the center of the chronic disease universe

Over the past quarter century it has become clear that adult onset chronic diseases like heart disease and type 2 diabetes have their roots in early development. The report by David Barker and colleagues showing an inverse relationship between birthweight and mortality from ischemic heart disease was the first clear-cut demonstration of fetal programming. Because fetal growth depends upon the placental capacity to transport nutrients from maternal blood, it has been a suspected causative agent since the original Barker reports. Epidemiological studies have shown that placental size and shape have powerful associations with offspring disease. More recent studies have shown that maternal phenotypic characteristics, such as body mass index and height, interact with placental size and shape to predict disease with much more precision than does birthweight alone. For example, among people in the Helsinki Birth Cohort, who were born during 1924–1944, the risk for acquiring colorectal cancer increased as the placental surface became longer and more oval. Among people in whom the difference between the length and breadth of the surface exceeded 6 cm, the hazard ratio for the cancer was 2.3 (95% CI 1.2–4.7, p=0.003) compared with those in whom there was no difference. Among Finnish men, the hazard ratio for coronary heart disease was 1.07 (1.02–1.13, P =0.01) per 1% increase in the placental weight/birthweight ratio. Thus, it appears that the ratio of birthweight to placental weight, known as placental efficiency, predicts cardiovascular risk as well. Babies born with placentas at the extremes of efficiency are more vulnerable for adult onset chronic diseases. Recent evidence suggests that placental growth patterns are sex specific. Boys’ placentas are, in general, more efficient than those made by girls. Another recent discovery is that the size, shape and efficiencies of the placenta can change over years of time with very narrow confidence limits. This suggests that the growth of the placenta within a population of women is strongly affected by their nutritional environment. Even though it is known that an individual placenta can expand to improve its nutrient acquisition capacity in the first 2/3rd of gestation, the mechanisms by which placentas grow in response to a specific nutritional environment are not known. Discovering those mechanisms is the task of the current generation of scientists. While it may seem obvious that good nutrition is highly important for women who are pregnant because it supports optimal placentation and fetal development, more research is needed to determine the mechanisms by which maternal nutrition, placenta growth and fetal health are related.