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Preterm birth is associated with epigenetic programming of transgenerational hypertension in mice.
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-01-24 , DOI: 10.1038/s12276-020-0373-5 Laurence Dumeige 1, 2 , Mélanie Nehlich 1, 2 , Say Viengchareun 1, 2 , Julie Perrot 1 , Eric Pussard 1, 2, 3, 4 , Marc Lombès 1, 2, 4, 5 , Laetitia Martinerie 1, 2, 5, 6, 7
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-01-24 , DOI: 10.1038/s12276-020-0373-5 Laurence Dumeige 1, 2 , Mélanie Nehlich 1, 2 , Say Viengchareun 1, 2 , Julie Perrot 1 , Eric Pussard 1, 2, 3, 4 , Marc Lombès 1, 2, 4, 5 , Laetitia Martinerie 1, 2, 5, 6, 7
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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.
中文翻译：
早产与小鼠跨代高血压的表观遗传编程有关。
早产的肾脏和心血管并发症已得到充分证实，尤其是成年后高血压的发展。但是，基本的分子机制仍然知之甚少。我们的目的是研究早产对肾皮质类固醇途径本体发育的影响，评估其在围产期肾并发症和成年高血压中的作用。在怀孕18天（E18），给瑞士CD1怀孕的小鼠注射脂多糖，以诱导其在E18.5早产。在出生，7天和6个月的生命中处死幼仔。还分析了通过将早产成年雌性与野生型雄性交配而建立的第二代（F2）和第三代（F3）。前早产男性在M6时出现高血压（P <0.0001）。我们发现早产小鼠（αENaC（+45％），Gilz（+ 85％））出生时肾皮质类固醇靶基因转录的强劲激活，与盐皮质激素或糖皮质激素受体表达的任何变化无关。尽管通过LC-MS / MS测量的MR或GR表达和血浆皮质类固醇水平相似，早产组的后代仍显示F2和F3血压升高，与肾脏Gilz mRNA表达增加有关。通过甲基化的DNA免疫沉淀-qPCR测定的Gilz启动子甲基化减少，甲基化与表达之间呈负相关（P = 0.0106）。我们的研究表明，肾皮质类固醇信号通路中的早产相关改变，直到第三代为止，血压失调和表观遗传的吉尔兹调节都可以遗传。
更新日期：2020-01-24
中文翻译：
早产与小鼠跨代高血压的表观遗传编程有关。
早产的肾脏和心血管并发症已得到充分证实，尤其是成年后高血压的发展。但是，基本的分子机制仍然知之甚少。我们的目的是研究早产对肾皮质类固醇途径本体发育的影响，评估其在围产期肾并发症和成年高血压中的作用。在怀孕18天（E18），给瑞士CD1怀孕的小鼠注射脂多糖，以诱导其在E18.5早产。在出生，7天和6个月的生命中处死幼仔。还分析了通过将早产成年雌性与野生型雄性交配而建立的第二代（F2）和第三代（F3）。前早产男性在M6时出现高血压（P <0.0001）。我们发现早产小鼠（αENaC（+45％），Gilz（+ 85％））出生时肾皮质类固醇靶基因转录的强劲激活，与盐皮质激素或糖皮质激素受体表达的任何变化无关。尽管通过LC-MS / MS测量的MR或GR表达和血浆皮质类固醇水平相似，早产组的后代仍显示F2和F3血压升高，与肾脏Gilz mRNA表达增加有关。通过甲基化的DNA免疫沉淀-qPCR测定的Gilz启动子甲基化减少，甲基化与表达之间呈负相关（P = 0.0106）。我们的研究表明，肾皮质类固醇信号通路中的早产相关改变，直到第三代为止，血压失调和表观遗传的吉尔兹调节都可以遗传。
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