Environmental influences on renal tract development: a focus on maternal diet and the glucocorticoid hypothesis

Woolf, Adrian S.

doi:10.1055/s-0030-1255876

Cited by 8 publications

(8 citation statements)

References 44 publications

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“…Our hypothesis is that the fetal milieu influences the tempo of kidney cystogenesis. When developing kidneys of wild-type animals are exposed to adverse environments, their growth and differentiation trajectories deviate from normal [12], [13]. Low protein diet (LPD) administered to pregnant animals is a much studied model of fetal programming [14].…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo Modeling of Chemical Synergy in Prenatal Kidney Cystogenesis

et al. 2013

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Cyclic adenosine monophosphate (cAMP) drives genetic polycystic kidney disease (PKD) cystogenesis. Yet within certain PKD families, striking differences in disease severity exist between affected individuals, and genomic and/or environmental modifying factors have been evoked to explain these observations. We hypothesized that PKD cystogenesis is accentuated by an aberrant fetal milieu, specifically by glucocorticoids. The extent and nature of cystogenesis was assessed in explanted wild-type mouse embryonic metanephroi, using 8-Br-cAMP as a chemical to mimic genetic PKD and the glucocorticoid dexamethasone as the environmental modulator. Cysts and glomeruli were quantified by an observer blinded to culture conditions, and tubules were phenotyped using specific markers. Dexamethasone or 8-Br-cAMP applied on their own produced cysts predominantly arising in proximal tubules and descending limbs of loops of Henle. When applied together, however, dexamethasone over a wide concentration range synergized with 8-Br-cAMP to generate a more severe, glomerulocystic, phenotype; we note that prominent glomerular cysts have been reported in autosomal dominant PKD fetal kidneys. Our data support the idea that an adverse antenatal environment exacerbates renal cystogenesis.

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Section: Introductionmentioning

confidence: 99%

Ex Vivo Modeling of Chemical Synergy in Prenatal Kidney Cystogenesis

et al. 2013

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“…Glucocorticoids activate the renin-angiotensin system 12 , 39 and change the hypothalamic-pituitary-adrenal axis 13 as well as the vascular system, causing endothelial damage and increasing arterial tension 40 , which may impact renal function later in life. Additionally, considering that renal differentiation in mice can also be affected by a low-protein maternal diet 41 , 42 , the impact may occur even without centralization in exposed fetuses. Because adults born small for gestational age have a diminished renal reserve to manage any mechanism of renal damage in future life, any further risk factor, such as chronic hypertension and nephrotoxic drugs, may impact renal function 6 , 7 , 43 .…”

Section: Resultsmentioning

confidence: 99%

An unfavorable intrauterine environment may determine renal functional capacity in adulthood: a meta-analysis

Senra¹,

Carvalho²,

Rodrigues³

et al. 2018

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Since studies show that an unfavorable environment during intrauterine development predisposes individuals to several diseases in adulthood, our objective is to assess the relation between fetal growth restriction and chronic renal disease in adults. We searched four different electronic databases through November 2017: CENTRAL, EMBASE, LILACS and MEDLINE. We selected studies with longitudinal or transversal designs associating kidney function in adulthood with low birth weight. Two reviewers evaluated the inclusion criteria and the risk of bias and extracted data from the included papers. Thirteen studies were selected for the systematic review and meta-analysis. We observed increased risks of presenting end-stage renal disease (risk ratio 1.31, 95% confidence interval: 1.17, 1.47), a lower glomerular filtration rate (ml/min) (mean difference 7.14; 95% confidence interval: -12.12, -2.16), microalbuminuria (risk ratio 1.40; 95% confidence interval: 1.28, 1.52) and a small increase in the albumin/creatinine ratio (mean difference 0.46; 95% confidence interval: 0.03, 0.90) in the low birth weight patients, compared with control group. These findings suggest that low birth weight is associated with renal dysfunction in adults.

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“…The first of these was embryonic day 13 (E13) wild-type CD1 mouse metanephroi explanted in organ culture and grown in serum-free, defined media containing 0.47 μM dexamethasone, as previously described [22]. In this model, which may represent a paradigm for the modulation of cystogenesis by glucocorticoid "foetal programming" [24], nephrons become cystic after 6 days in culture [22]. The second model was 8-week-old wild-type and PCK homozygous mutant kidneys (Charles River) which contain predominantly distal nephron and collecting duct cysts [25].…”

Section: Methodsmentioning

confidence: 99%

An unusual case of pediatric shortness of breath—questions

2011

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BackgroundFraser syndrome (FS) features renal agenesis and cystic kidneys. Mutations of FRAS1 (Fraser syndrome 1) and FREM2 (FRAS1-related extracellular matrix protein 2) cause FS. They code for basement membrane proteins expressed in metanephric epithelia where they mediate epithelial/mesenchymal signalling. Little is known about whether and where these molecules are expressed in more mature kidneys.MethodsIn healthy and congenital polycystic kidney (cpk) mouse kidneys we sought Frem2 expression using a LacZ reporter gene and quantified Fras family transcripts. Fras1 immunohistochemistry was undertaken in cystic kidneys from cpk mice and PCK (Pkhd1 mutant) rats (models of autosomal recessive polycystic kidney disease) and in wild-type metanephroi rendered cystic by dexamethasone.ResultsNascent nephrons transiently expressed Frem2 in both tubule and podocyte epithelia. Maturing and adult collecting ducts also expressed Frem2. Frem2 was expressed in cpk cystic epithelia although Frem2 haploinsufficiency did not significantly modify cystogenesis in vivo. Fras1 transcripts were significantly upregulated, and Frem3 downregulated, in polycystic kidneys versus the non-cystic kidneys of littermates. Fras1 was immunodetected in cpk, PCK and dexamethasone-induced cyst epithelia.ConclusionsThese descriptive results are consistent with the hypothesis that Fras family molecules play diverse roles in kidney epithelia. In future, this should be tested by conditional deletion of FS genes in nephron segments and collecting ducts.

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Environmental influences on renal tract development: a focus on maternal diet and the glucocorticoid hypothesis

Cited by 8 publications

References 44 publications

Ex Vivo Modeling of Chemical Synergy in Prenatal Kidney Cystogenesis

Ex Vivo Modeling of Chemical Synergy in Prenatal Kidney Cystogenesis

An unfavorable intrauterine environment may determine renal functional capacity in adulthood: a meta-analysis

An unusual case of pediatric shortness of breath—questions

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