Intrauterine growth restriction modifies the normal gene expression in kidney from rabbit fetuses

Figueroa, H.; Lozano, Mauricio; Suazo, Cristián; Eixarch, Elisenda; Illanes, Sebastián E.; Carreño, Juan; Villanueva, Sandra; Hernández‐Andrade, Edgar; Gratacós, E.; Irarrázabal, Carlos E.

doi:10.1016/j.earlhumdev.2012.07.010

Cited by 20 publications

(37 citation statements)

References 41 publications

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“…An IUGR model was created as previously described [4]. Briefly, fetal growth restriction was induced in pregnant rabbits at 25 days of gestation in which uteroplacental vessels of one horn were ligated at 40-50% and the contralateral horn was considered as controls.…”

Section: Rabbit Iugr Modelmentioning

confidence: 99%

“…It is defined as the new onset of hypertension accompanied by proteinuria during the second half of pregnancy and it affects 5-8% of all pregnancies causing nearly 40% of premature births [2,3]. PE is associated with fetal complications such as intrauterine growth restriction (IUGR), a common diagnosis in obstetrics that carries an increased risk of neonatal complications including stillbirth, birth hypoxia and impaired neurodevelopment [4]. PE has been also strongly associated with increased maternal risk of later-life death due to cardiovascular disease, independently of other risk factors [5].…”

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confidence: 99%

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NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction1

Dobierzewska

Palominos

Irarrázabal

et al. 2015

Biology of Reproduction

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During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A.

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Section: Rabbit Iugr Modelmentioning

confidence: 99%

mentioning

confidence: 99%

NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction1

Dobierzewska

Palominos

Irarrázabal

et al. 2015

Biology of Reproduction

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“…Low oxygen levels have been shown to increase [14][15][16] or decrease UB branching of ex vivo cultured metanephric kidneys. 15,16 In a model of intrauterine growth restriction, nephron number was significantly reduced in the presence of increased levels of HIF-1α, 17 but whether this association between HIF-1α expression and impaired nephrogenesis is causal cannot be inferred from these findings.…”

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confidence: 97%

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

Schley

Scholz

Kraus

et al. 2015

Kidney International

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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.

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“…Research over the past decade has provided substantial data showing that AKI leads to CKD (2)(3)(4)(5)(6)(7)(8). Although the exact mechanisms underlying the progression from AKI to CKD continue to be explored, endothelial damage may play a critical role in outcomes, leading to nephron drop-out, interstitial fibrosis, and, ultimately, CKD (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). A full review of the data on the link between AKI and CKD in animals and adults is beyond the scope of this article but has recently been performed (5).…”

Section: Statement Of the Problemmentioning

confidence: 99%

“…Thus, premature infants <34 wk are at risk for CKD due to lesser number of nephron. Intrauterine growth retardation affects gene expression and nephron endowment, and filtration surface area (12,13) are decreased in animals with intrauterine growth retardation. The timing of the growth restriction may be a key element affecting renal development.…”

Section: Statement Of the Problemmentioning

confidence: 99%

Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury

et al. 2015

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Intrauterine growth restriction modifies the normal gene expression in kidney from rabbit fetuses

Cited by 20 publications

References 41 publications

NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction1

NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction1

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

Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury

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