ESPE Abstracts

Introduction: Prematurity, a worldwide health issue, is often associated with renal tubular immaturity leading to major salt loss, whose mechanisms remain poorly understood. Moreover, these premature infants are prone to develop hypertension early in adulthood.

Objective: To study the ontogenesis of renal mineralocorticoid and glucocorticoid signaling pathways in preterm infants and to evaluate their respective role during neonatal adaptation and in the emergence of hypertension in adulthood.

Materials and Methods: We have developed a model of prematurity induced by intra-peritoneal injection of O111:B4 lipopolysaccharides at 18 days of gestation in Swiss CD1 mice. Offspring of injected mice, when lipopolysaccharides did not trigger preterm birth, were used as a control to exclude the intrinsic LPS effects. Newborns were sacrificed at various developmental stages (P0, P7 and M6). Blood pressure and heart rate were measured in males at M6 and their plasma steroid profiles were determined using liquid chromatography-tandem mass spectrometry. Renal mRNA and protein expression of major players of corticosteroid signaling pathways were examined using RT-qPCR and western-blot analyses. A second (F2) and third (F3) generations, established by mating prematurely born adult female with wild type males, were also analyzed.

Results: As anticipated, premature newborn mice presented with maladaptation, as revealed by high neonatal mortality (35%), and a lower birth weight compared to controls (1.29±0.21 vs 1.46±0.15 g, 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 very robust activation of renal corticosteroid target genes transcription at birth in premature mice (αENaC (+45%), Sgk1 (+132%), Gilz (+85%)), which was not related to modified expressions of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). Such alterations of gene expression were not persistent in adulthood. Interestingly, a significant increased blood pressure was found in the F2 and F3 males, descendants of the preterm group, concomitantly with alteration of renal Sgk1 and Gilz mRNA and protein expressions, despite absence of modifications in MR and GR expression and similar aldosterone and corticosterone plasma levels than descendants from the control group. These results are highly suggestive of trans-generational epigenetic inheritance, mechanisms of which are presently under investigation.

Conclusion: We provide evidence for tissue-specific alterations of the renal corticosteroid signaling pathways induced by prematurity, with a trans-generational transmission. These studies should allow better understanding of prematurity-related defects, leading hopefully to better management of premature infants from birth to adulthood.