Preterm birth is associated with epigenetic programming of transgenerational hypertension in mice

Abstract

Renal and cardiovascular complications of prematurity are well established, notably the development of hypertension in adulthood. However, the underlying molecular mechanisms remain poorly understood. Our objective was to investigate the impact of prematurity on the ontogenesis of renal corticosteroid pathways, to evaluate its implication in perinatal renal complications and in the emergence of hypertension in adulthood. Swiss CD1 pregnant mice were injected with lipopolysaccharides at 18 days of gestation (E18) to induce prematurity at E18.5. Pups were sacrificed at birth, 7 days and 6 months of life. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild-type males, were also analyzed. Former preterm males developed hypertension at M6 (P < 0.0001). We found robust activation of renal corticosteroid target gene transcription at birth in preterm mice (αENaC (+45%), Gilz (+85%)), independent of any change in mineralocorticoid or glucocorticoid receptor expression. The offspring of the preterm group displayed increased blood pressure in F2 and F3, associated with increased renal Gilz mRNA expression, despite similar MR or GR expression and plasma corticosteroid levels measured by LC-MS/MS. Gilz promoter methylation measured by methylated DNA immunoprecipitation-qPCR was reduced with a negative correlation between methylation and expression (P = 0.0106). Our study demonstrates prematurity-related alterations in renal corticosteroid signaling pathways, with transgenerational inheritance of blood pressure dysregulation and epigenetic Gilz regulation up to the third generation. This study provides a better understanding of the molecular mechanisms involved in essential hypertension, which could partly be due to perinatal epigenetic programming from previous generations.

Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

“…There is a timely requirement for gene transcription regulation during normal development. In this case, only the genes that are specific to a particular cell type and developmental stage are transcriptionally active [84,85]. The ability to conduct gene transcriptional modulation provides "plasticity" during development [86,87].…”

The association of gestational age and birthweight with blood pressure, cardiac structure, and function in 4 years old: a prospective birth cohort study

“…This phenomenon is particularly interesting. It can be hypothesized that the mechanism is as follows: GA mainly influences children by the duration of the intra or extra uterine environmental exposure and affects the degree of fetal organ development through perinatal reprogramming [ 43 ]. It is determined by the maternal and/or fetal health condition.…”

Sexual Dimorphism of Corticosteroid Signaling during Kidney Development

“…These sex differences are not linked to a variability in HPA axis function [ 33 ], but they may be in relation with a higher sensitivity to the administration of antenatal corticosteroids in boys [ 124 ]. In a model of lipopolysaccharide-induced prematurity, generated by our group, we observed that former preterm males develop significant hypertension in adulthood [ 125 ]. This hypertension is associated with early changes in the expression of different players of the corticosteroid signaling pathway during the neonatal period.…”

“…In our mouse model, we identified a transmission of blood pressure dysregulation to subsequent generations from preterm neonates, up to the third generation. Interestingly, this vascular anomaly was only transmitted in males in the second and third generation, which is associated with a significant increase in expression of the corticosteroid target gene Gilz and a global hypomethylation of its promoter [ 125 ]. This study demonstrates that a predisposition to arterial hypertension could be epigenetically programmed in males by events occurring during the perinatal period in previous generations through sexually dimorphic adverse activation of corticosteroid signaling pathway.…”