Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric β-catenin signaling

Wilkinson, Lorine; Neal, Cailda S.; Singh, Reetu R.; Sparrow, Duncan B.; Kurniawan, Nyoman D.; Ju, Adler; Grieve, Stuart M.; Dunwoodie, Sally L.; Moritz, Karen M.; Little, Melissa H.

doi:10.1038/ki.2014.394

Cited by 42 publications

(50 citation statements)

References 57 publications

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“…However, the acid maceration technique was used to quantity nephron number, which is not as reliable as the physical-disector fractionator method, the current gold standard of glomerular number estimation . In a recent study, midgestation, moderate hypoxia (E12.5, 12% maternal O 2 ) for 48 hours in the mouse caused fetal growth restriction, suppression of branching morphogenesis in the kidney and reduced nephron number (Wilkinson et al, 2015). The same study also demonstrated that severe, short-term hypoxia (5.5-7.5% maternal O 2 for 10 h from E9.5-10.5) resulted in congenital abnormalities of the kidney and urinary tract.…”

Section: Effects Of Prenatal Hypoxia On the Kidneymentioning

confidence: 56%

“…We confirmed, using unbiased stereology, that the number of glomeruli per kidney in the male hypoxia-exposed mice was reduced by ~25%. This is an equivalent reduction in glomerular number to that seen in mice exposed to transient mid-gestational hypoxia (males and females combined) (Wilkinson et al, 2015), and in males offspring following uteroplacental insufficiency in the rat (Wlodek et al, 2007). However, female hypoxia-exposed offspring presented with number of glomeruli per kidney similar to that of the control offspring suggesting that gender is somewhat protective against the hypoxic insult induced throughout late gestation.…”

Section: Sex Specific Reductions In Nephron Number Following Prenatalmentioning

confidence: 74%

“…Maternal hypoxia (Wilkinson et al, 2015) Mouse Pooled ↓ ↓ --Cigarette smoke exposure (Al-Odat et al, 2014) Rat Males ↔ ↓ Albuminuria -Uteroplacental insufficiency Moritz et al, 2009a) Rat Males Females ↓ ↓ ↑ plasma creatinine, aged females ↑ SBP in males GLUCOCORTICOID EXPOSURE Dexamethasone Sheep Females ↔ ↓ 38% -↑ 10 mmHg Betamethasone …”

Section: Hypoxiamentioning

confidence: 99%

“…In the human population, low birth weight is associated with reduced glomerular number, glomerular hypertrophy, glomerulosclerosis, albuminuria and elevated blood pressure . We have previously reported that severe earlygestational hypoxia (5.5-7.5% O 2 , embryonic day 9.5-10.5) and moderate mid-gestational hypoxia (12% O 2 , embryonic day 12.5-14.5) in the mouse causes a reduction in nephron number and leads to similar structural phenotypes seen in patients with congenital anomalies of the kidney and urinary tract (CAKUT) (Wilkinson et al, 2015). However, the consequences of prenatal hypoxia on renal and cardiovascular function have not been followed up long-term in these offspring.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, maternal ethanol consumption during mid-gestation in the rat was associated with reduced expression of the branching morphogenesis gene Gdnf and its receptor, c-Ret . Mid-gestational transient hypoxia (12% O 2 , 48 h, 12.5-14.5) was shown to reduce ureteric branching and glomerular number in mouse offspring (Wilkinson et al, 2015). This was driven by suppression of β-catenin signalling, which contributes to branching morphogenesis, nephron induction, nephron elongation and medullary development (Park et al, 2007;Bridgewater et al, 2008;Marose et al, 2008).…”

Section: Molecular Mechanisms Contributing To Altered Renal Developmentmentioning

confidence: 99%

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Gestational hypoxia and programming of disease

Walton¹

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Fetal hypoxia remains the most common complication throughout pregnancy and has a wide aetiology including, but not limited to, placental insufficiency, high altitude living and maternal factors such as smoking and pulmonary disease. Intrauterine growth restriction and subsequent low birth weight are common features of pregnancies complicated by reduced oxygenation. Suboptimal organ development may arise, thereby substantially increasing vulnerability to cardiovascular and renal diseases in adulthood. Recently it has been established that prenatally programmed vulnerability to disease may be exacerbated by a postnatal 'second-hit', such as a high salt diet or ageing. The primary aim of this thesis was to investigate the effects of maternal hypoxia on the programming of cardiovascular and renal disease in mice, and secondly whether excess dietary salt intake throughout life may exacerbate disease outcomes.Pregnant CD1 mice were housed in a hypoxia chamber set to 12% oxygen throughout the last five days of pregnancy, from embryonic day (E) 14.5 until birth (P0). Control animals remained in normoxic room conditions (21% oxygen) throughout pregnancy. Upon littering, animals were removed from the hypoxia chamber and raised in normoxic room conditions. A subset of mice was fed a high salt diet from 10 weeks of age until post-mortem. Mice were housed in metabolic cages for 24 hours to assess renal function under basal conditions, and in response to a 24 hour water deprivation challenge, at 4 and 12 months of age. Blood pressure and microvascular function and structure were assessed in offspring at 12 months of age.Kidneys, hearts and aortas were collected for stereological and histological analyses.Prenatal hypoxia reduced nephron number in the kidneys of male offspring, leading to glomerular hypertrophy, renal fibrosis and mild albuminuria by 12 months of age. However, female offspring exposed to the same hypoxic insult in utero presented with normal number of glomeruli and renal pathology equivalent to control animals by 12 months of age. Both male and female hypoxia-exposed offspring had elevated mean arterial pressure at 12 months of age. A high salt diet throughout adult life increased cardiac tissue fibrosis, particularly in male hypoxia-exposed offspring, and exacerbated renal pathology in male hypoxia-exposed offspring only. Pressurized myography was performed at the time of post-mortem to assess functional, structural and mechanical properties of mesenteric resistance arteries at 12 months of age. Both male and female offspring exposed to maternal hypoxia had significantly 3 impaired endothelial function, which was not exacerbated by the high salt diet. The combination of prenatal hypoxia and a postnatal high salt diet caused marked stiffening of the microvasculature as well as loss of elastin integrity and increased collagen content in the aorta, consistent with vascular stiffness. This suggests that kidneys from female offspring are somehow protected from the in utero insult; however, this protection...

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Section: Effects Of Prenatal Hypoxia On the Kidneymentioning

confidence: 56%

Section: Sex Specific Reductions In Nephron Number Following Prenatalmentioning

confidence: 74%

Section: Hypoxiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Molecular Mechanisms Contributing To Altered Renal Developmentmentioning

confidence: 99%

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Gestational hypoxia and programming of disease

Walton¹

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Maternal hypoxia developmentally programs low podocyte endowment in male, but not female offspring

Gonçalves

Walton

Gazzard

et al. 2020

The Anatomical Record

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Fetal hypoxia is a common complication of pregnancy. We have previously reported that maternal hypoxia in late gestation in mice gives rise to male offspring with reduced nephron number, while females have normal nephron number. Male offspring later develop proteinuria and renal pathology, including glomerular pathology, whereas female offspring are unaffected. Given the central role of podocyte depletion in glomerular and renal pathology, we examined whether maternal hypoxia resulted in low podocyte endowment in offspring. Pregnant CD1 mice were allocated at embryonic day 14.5 to normoxic (21% oxygen) or hypoxic (12% oxygen) conditions. At postnatal day 21, kidneys from mice were immersion fixed, and one mid‐hilar slice per kidney was immunostained with antibodies directed against p57 and synaptopodin for podocyte identification. Slices were cleared and imaged with a multiphoton microscope for podometric analysis. Male hypoxic offspring had significantly lower birth weight, nephron number, and podocyte endowment than normoxic male offspring (podocyte number; normoxic 62.86 ± 2.26 podocytes per glomerulus, hypoxic 53.38 ± 2.25; p < .01, mean ± SEM). In contrast, hypoxic female offspring had low birth weight but their nephron and podocyte endowment was the same as normoxic female offspring (podocyte number; normoxic 62.38 ± 1.86 podocytes per glomerulus, hypoxic 61.81 ± 1.80; p = .88). To the best of our knowledge, this is the first report of developmentally programmed low podocyte endowment. Given the well‐known association between podocyte depletion in adulthood and glomerular pathology, we postulate that podocyte endowment may place offspring at risk of renal disease in adulthood, and explain the greater vulnerability of male offspring.

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Oxygen and lack of oxygen in fetal and placental development, feto–placental coupling, and congenital heart defects

Olivé

Xiao

Natale

et al. 2018

Birth Defects Research

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Low oxygen concentration (hypoxia) is part of normal embryonic development, yet the situation is complex. Oxygen (O2) is a janus gas with low levels signaling through hypoxia‐inducible transcription factor (HIF) that are required for development of fetal and placental vasculature and fetal red blood cells. This results in coupling of fetus and mother around midgestation as a functional feto‐placental unit (FPU) for O2 transport, which is required for continued growth and development of the fetus. Defects in these processes may leave the developing fetus vulnerable to O2 deprivation or other stressors during this critical midgestational transition when common septal and conotruncal heart defects (CHDs) are likely to arise. Recent human epidemiological and case–control studies support an association between placental dysfunction, manifest as early onset pre‐eclampsia (PE) and increased serum bio‐markers, and CHD. Animal studies support this association, in particular those using gene inactivation in the mouse. Sophisticated methods for gene inactivation, cell fate mapping, and a quantitative bio‐reporter of O2 concentration support the premise that hypoxic stress at critical stages of development leads to CHD. The secondary heart field contributing to the cardiac outlet is a key target, with activation of the un‐folded protein response and abrogation of FGF signaling or precocious activation of a cardiomyocyte transcriptional program for differentiation, suggested as mechanisms. These studies provide a strong foundation for further study of feto–placental coupling and hypoxic stress in the genesis of human CHD.

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Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric β-catenin signaling

Cited by 42 publications

References 57 publications

Gestational hypoxia and programming of disease

Gestational hypoxia and programming of disease

Maternal hypoxia developmentally programs low podocyte endowment in male, but not female offspring

Oxygen and lack of oxygen in fetal and placental development, feto–placental coupling, and congenital heart defects

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