High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome

Escher, Geneviève; Cristiano, Martino; Causevic, Maja; Baumann, Marc; Frey, Felix J.; Surbek, Daniel; Mohaupt, Markus

doi:10.1093/ndt/gfn763

Cited by 30 publications

(29 citation statements)

References 34 publications

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“…As both high aldosterone levels and enhanced Na + intake have been linked to improved pregnancy outcome and reduced BP, it is unclear whether Na + or aldosterone is primarily responsible 7, 8, 9, 10, 11. A beneficial role of an increased Na + uptake during pregnancy was postulated,10 yet to what extent of Na + intake remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy

Eisele

Klossner

Escher

et al. 2018

JAHA

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BackgroundIn pregnancy, a high plasma volume maintains uteroplacental perfusion and prevents placental ischemia, a condition linked to elevated maternal blood pressure (BP). Reducing BP by increasing Na+ intake via plasma volume expansion appears contra‐intuitive. We hypothesize that an appropriate Na+ intake in pregnancy reduces maternal BP and adapts the renin‐angiotensin system in a pregnancy‐specific manner.Methods and Results BP was measured by implanted telemetry in Sprague‐Dawley rats before and throughout pregnancy. Pregnant and nonpregnant animals received either a normal‐salt (0.4%; NS), high‐salt (8%; HS), or low‐salt (0.01%; LS) diet, or HS (days 1–14) followed by LS (days 14–20) diet (HS/LS). Before delivery (day 20), animals were euthanized and organs collected. Food, water, and Na+ intake were monitored in metabolic cages, and urinary creatinine and Na+ were analyzed. Na+ intake and retention increased in pregnancy (NS, LS), leading to a positive Na+ balance (NS, LS). BP was stable during LS, but reduced in HS conditions in pregnancy. The renin‐angiotensin system was adapted as expected. Activating cleavage of α‐ and γ‐subunits of the renal epithelial Na+ channel and expression of‐full length medullary β‐subunits, accentuated further in all LS conditions, were upregulated in pregnancy.ConclusionsPregnancy led to Na+ retention adapted to dietary changes. HS exposure paradoxically reduced BP. Na+ uptake while only modestly linked to the renin‐angiotensin system is enhanced in the presence of posttranslational renal epithelial Na+ channel modifications. This suggests (1) storage of Na+ in pregnancy upon HS exposure, bridging periods of LS availability; and (2) that potentially non–renin‐angiotensin–related mechanisms participate in ENaC activation and consecutive Na+ retention.

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Section: Introductionmentioning

confidence: 99%

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy

Eisele

Klossner

Escher

et al. 2018

JAHA

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“…The frequency of the MR L810 between the two groups was not different (12% vs 9.4%) ( Table 3). On the other hand, Schmider-Ross et al, 22 in 38 patients with pregnancy-induced hypertension, as well as Escher et al, 19 in 48 preeclamptic women, were not able to detect the MR L810 mutation. Although those studies were inconclusive, the earlier observation that progesterone levels were significantly elevated in preeclamptic women 7 prompted us to address the MR L810 mutation frequency in hypertensive women.…”

Section: Discussionmentioning

confidence: 92%

“…19 They conclude that the gain-of-function variants of the CYP11B2 reduce the risk for developing preeclampsia. 19 In contrast, the genetic polymorphism V386A in exon 7 of CYP11B2 was detected in 17% of preeclamptic women. 6 This polymorphism has been investigated in vitro and has shown to reduce, but not abrogate CYP11B2 activity in cell cultures.…”

Section: Discussionmentioning

confidence: 99%

“…Escher et al 19 found that a high aldosterone availability is associated with lower C-344T CYP11B2 and S810L MR in gestational hypertension M Ramı´rez-Salazar et al maternal blood pressure, and that the -344C/T genotype is more frequent in women with preeclampsia, while the presence of the wild type (wt/wt) of the intron 2 conversion polymorphism predisposed to preeclampsia. 19 They conclude that the gain-of-function variants of the CYP11B2 reduce the risk for developing preeclampsia. 19 In contrast, the genetic polymorphism V386A in exon 7 of CYP11B2 was detected in 17% of preeclamptic women.…”

Section: Discussionmentioning

confidence: 99%

“…17 The studies on the association of this CYP11B2 gene polymorphism with gestational hypertension or preeclampsia are scant and remain controversial. Vasconcelos et al 18 did not find a significant association between the -344C/T polymorphism and gestational hypertension or preeclampsia, whereas Escher et al 19 found that the -344C/T genotype is increased, and the -344T/T genotype distribution is lower in the preeclamptic women as compared with normal pregnant women. Percin et al 20 studied women with preeclampsia, eclampsia and the HELLP syndrome and found that the CYP11B2 gene polymorphism is not directly associated with these conditions.…”

Section: Introductionmentioning

confidence: 94%

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Relationship of aldosterone synthase gene (C-344T) and mineralocorticoid receptor (S810L) polymorphisms with gestational hypertension

et al. 2010

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The extent of genetic influence in the aetiology of gestational hypertension has not been completely determined. The aim of this study was to analyse the relationship between aldosterone levels and the -344T/C polymorphism of the aldosterone synthase gene (CYP11B2) and to investigate the frequency of the S810L mutation of mineralocorticoid receptor (MR) in gestational hypertension. One hundred women with pregnancy-induced hypertension and 100 with normal pregnancy were studied to measure serum aldosterone and progesterone levels and for the genotypification of the -344T/C polymorphism of CYP11B2 gene and the S810L mutation of MR by RFLP-PCR and SSP, respectively. Serum aldosterone levels were reduced (o0.000001) and serum progesterone levels increased (o0.000001) in gestational hypertensive women as compared with normal pregnant women. The -344T/C of CYP11B2 genotypic frequencies were similar in the hypertensive and normotensive pregnant women. The 810L-mutated allele of MR was found in 12% of the hypertensive and 9.4% of the normotensive pregnant women. In contrast to the observations made in preeclampsia, the genotype of -344T/C of CYP11B2 was neither related with gestational hypertension nor with aldosterone levels at delivery. The frequency of the S810L mutation was similar in the hypertensive and normotensive women but higher than observed in other reports.

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Aldosterone deficiency adversely affects pregnancy outcome in mice

Todkar

Chiara

Loffing‐Cueni

et al. 2012

Pflugers Arch - Eur J Physiol

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Circulating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase-deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/-) offspring. With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High-salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and abolished the difference in blood pressure during late pregnancy. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall, an increased placental efficiency was observed in both groups paralleled by a normalization of elevated HIF1 levels in the AS(-/-) placentas. Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function. In this animal model, aldosterone deficiency did not cause preeclampsia. ABSTRACTCirculating aldosterone levels are increased in human pregnancy. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity.Moreover, inactivating polymorphisms in the aldosterone synthase gene have been detected in preeclamptic women. Here, we used aldosterone synthase deficient

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High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome

Cited by 30 publications

References 34 publications

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy

Relationship of aldosterone synthase gene (C-344T) and mineralocorticoid receptor (S810L) polymorphisms with gestational hypertension

Aldosterone deficiency adversely affects pregnancy outcome in mice

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