The effects of gestational age and maternal hypoxia on the placental renin angiotensin system in the mouse

Prenatal hypoxia is a common perturbation to arise during pregnancy, and can lead to adverse health outcomes in later life. The long-lasting impact of prenatal hypoxia on postnatal kidney development and maturation of the renal tubules, particularly the collecting duct system, is relatively unknown. In the present study, we used a model of moderate chronic maternal hypoxia throughout late gestation (12% O exposure from embryonic day 14.5 until birth). Histological analyses revealed marked changes in the tubular architecture of male hypoxia-exposed neonates as early as postnatal day 7, with disrupted medullary development and altered expression of Ctnnb1 and Crabp2 (encoding a retinoic acid binding protein). Kidneys of the RARElacZ line offspring exposed to hypoxia showed reduced β-galactosidase activity, indicating reduced retinoic acid-directed transcriptional activation. Wild-type male mice exposed to hypoxia had an early decline in urine concentrating capacity, evident at 4 months of age. At 12 months of age, hypoxia-exposed male mice displayed a compromised response to a water deprivation challenge, which was was correlated with an altered cellular composition of the collecting duct and diminished expression of aquaporin 2. There were no differences in the tubular structures or urine concentrating capacity between the control and hypoxia-exposed female offspring at any age. The findings of the present study suggest that prenatal hypoxia selectively disrupts collecting duct patterning through altered Wnt/β-catenin and retinoic acid signalling and this results in impaired function in male mouse offspring in later life.

Section: Discussionmentioning

confidence: 99%

“…We have described adverse outcomes on renal and cardiovascular function in a mouse model of moderate, late‐gestational hypoxia [12% O 2 for 5 days, embryonic day (E) 14.5 to birth] (Cuffe et al . 2014a; Cuffe et al . 2014b; Walton et al .…”

Section: Introductionmentioning

confidence: 99%

Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring

Walton

Singh

Little

et al. 2018

“…As previous studies have demonstrated that male‐ and female‐associated placentae respond differently to several pregnancy perturbations, we additionally characterized whether these responses were different in male‐ and female‐associated placentae (Cuffe et al . , ; Gardebjer et al . ).…”

Section: Introductionmentioning

confidence: 99%

Maternal exercise in rats upregulates the placental insulin‐like growth factor system with diet‐ and sex‐specific responses: minimal effects in mothers born growth restricted

Mangwiro

Cuffe

Briffa

et al. 2018

The insulin-like growth factor (IGF) system regulates fetoplacental growth and plays a role in disease programming. Dysregulation of the IGF system is implicated in several pregnancy perturbations associated with altered fetal growth, including intrauterine growth restriction and maternal obesity. Limited human studies have demonstrated that maternal exercise enhances fetoplacental growth and decreases cord IGF ligands, which may restore the placental IGF system in complicated pregnancies. This study investigated the impact maternal exercise has on the placental IGF system in placentae from mothers born growth restricted and if these outcomes are dependent on maternal diet or fetal sex. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning, and at 16 weeks were randomly allocated an exercise protocol: Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) with placentae associated with F2 fetuses collected at E20. The placental IGF system mRNA abundance and placental morphology was altered in mothers born growth restricted. Exercise increased fetal weight and Control plasma IGF1 concentrations, and decreased female placental weight. PregEx did not influence fetoplacental growth but increased placental IGF1 and IGF1R (potentially modulated by reduced Let 7f-1 miRNA) and decreased placental IGF2 protein. Importantly, these placental IGF system changes occurred with sex-specific responses. These data highlight that exercise differently influences fetoplacental growth and the placental IGF system depending on maternal exercise initiation, which may prevent the transgenerational transmission of deficits and dysfunction.

“…In the present study, we used our recently reported model of prenatal hypoxia in the mouse (Cuffe et al 2014a;Cuffe et al 2014b) to assess the impact of chronic late gestational hypoxia on microvascular structure and function in aged male and female offspring. In particular, we aimed to examine whether chronic high dietary sodium intake could exacerbate any deficits in microvascular structure and function.…”

Section: Introductionmentioning

confidence: 99%

Late gestational hypoxia and a postnatal high salt diet programs endothelial dysfunction and arterial stiffness in adult mouse offspring

Walton

Singh

Tan

et al. 2015

Key pointsr Maternal hypoxia is a common perturbation that leads to growth restriction and may program vascular dysfunction in adult offspring.r An adverse prenatal environment may render offspring vulnerable to increased cardiovascular risk when challenged with a 'second hit' , such as a high salt diet.r We investigated whether maternal hypoxia impaired vascular function, structure and mechanics in mouse offspring, and also whether this was exacerbated by excess dietary salt intake in postnatal life.r Maternal hypoxia predisposed adult male and female offspring to endothelial dysfunction. r The combination of prenatal hypoxia and high dietary salt intake caused significant stiffening of mesenteric arteries, and also altered structural characteristics of the aorta consistent with vascular stiffening.r The results of the present study suggest that prenatal hypoxia combined with a high salt diet in postnatal life can contribute to vascular dysfunction.Abstract Gestational hypoxia and high dietary salt intake have both been associated with impaired vascular function in adulthood. Using a mouse model of prenatal hypoxia, we examined whether a chronic high salt diet had an additive effect in promoting vascular dysfunction in offspring. Pregnant CD1 dams were placed in a hypoxic chamber (12% O 2 ) or housed under normal conditions (21% O 2 ) from embryonic day 14.5 until birth. Gestational hypoxia resulted in a reduced body weight for both male and female offspring at birth. This restriction in body weight persisted until weaning, after which the animals underwent catch-up growth. At 10 weeks of age, a subset of offspring was placed on a high salt diet (5% NaCl). Pressurized myography of mesenteric resistance arteries at 12 months of age showed that both male and female offspring exposed to maternal hypoxia had significantly impaired endothelial function, as demonstrated by impaired vasodilatation to ACh but not sodium nitroprusside. Endothelial dysfunction caused by prenatal hypoxia was not exacerbated by postnatal consumption of a high salt diet. Prenatal hypoxia increased microvascular stiffness in male offspring. The combination of prenatal hypoxia and a postnatal high salt diet caused a leftward shift in the stress-strain relationship in both sexes. Histopathological analysis of aortic sections revealed a loss of elastin integrity and increased collagen, consistent with increased vascular stiffness. These results demonstrate that prenatal * These authors contributed equally to this work. hypoxia programs endothelial dysfunction in both sexes. A chronic high salt diet in postnatal life had an additive deleterious effect on vascular mechanics and structural characteristics in both sexes.