ECE2019 Oral Communications Endocrine Connections 2 (5 abstracts)
Renal and cardio-vascular complications of prematurity are well established, notably those associated with renal tubular immaturity, responsible for major salt loss at birth, as well as early hypertension in adulthood. However, the molecular underlying mechanisms remain poorly understood. Our objective was to investigate the impact of preterm birth on the ontogenesis of renal corticosteroid pathways, to evaluate its implication on perinatal complications and on the emergence of hypertension in adulthood. Swiss CD1 pregnant mice were injected with O111:B4 lipopolysaccharides (LPS) at 18 days of gestation to induce preterm birth at 18.5 days of gestation. Offspring of injected mice, when LPS did not trigger preterm birth, were used as a control to exclude intrinsic LPS effects. Pups were sacrificed at various developmental stages (D0, D7 and M6). Blood pressure and heart rate were measured in males at M6 and their plasma steroid profiles were measured using LC-MSMS. Renal mRNA and protein expression of major players of corticosteroid signaling pathways were measured using RT-qPCR and western-blot analyses. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild type males, were also analyzed. We performed Methylation DNA Immunoprecipitation-qPCR to study the methylation status of candidate corticosteroid target genes that were differentially expressed between the two populations. As anticipated, preterm newborn mice presented with maladaptation, high neonatal mortality (35%), and a lower birth weight compared to controls (1.29±0.21 vs 1.46±0.15g, P=0.0027). Former preterm males developed hypertension at M6 (123.1±1.43 vs 114.5±0.79 mmHg, P<0.0001). We found a robust activation of renal corticosteroid target gene transcription at birth in preterm mice (αENaC (+45%), Sgk1 (+132%), Gilz (+85%)), which was not related to modified expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). Interestingly, a significant increased blood pressure was found in the F2 and F3 males, descendants of the preterm group, concomitantly with increased renal Gilz mRNA expression, despite similar MR or GR expression, and plasma aldosterone or corticosterone levels. Gilz promoter methylation was reduced in preterm offspring with a negative correlation between methylation and expression (P=0.008), highly suggestive of an epigenetic Gilz regulation. Our study demonstrates prematurity-related alterations of renal corticosteroid signaling pathways, with a transgenerational inheritance of blood pressure dysregulation and epigenetic Gilz regulation up to the third generation. This study should allow a better understanding of molecular mechanisms involved in essential hypertension, which could partly be due to perinatal epigenetic programming from previous generations.
18 May 2019 - 21 May 2019