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

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. A propensity towards high blood pressure may be passed down through several generations from adults who were born preterm. People who are born prematurely often suffer from kidney (renal) problems, high blood pressure and cardiovascular disease as they age. Recent research suggests adults born prematurely can pass dysregulated blood pressure to their children. Laetitia Martinerie at INSERM Unit 1185, Le Kremlin Bicetre and Robert Debre Hospital in Paris, France, and co-workers studied generations of mice to explore how epigenetic alterations, DNA modifications that do not change the DNA code, affect blood pressure from birth through to adulthood. The team identified tissue-specific alterations in renal signaling pathways in premature mice. They also traced the associated overexpression of a gene called Gilz, known to play a role in blood pressure maintenance, through second and third generation mice born to the first generation preterms.