Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo, Japan.
Department of Anatomy, Graduate School of Medicine, Teikyo University, Tokyo, Japan.
PLoS One. 2020 Aug 27;15(8):e0238223. doi: 10.1371/journal.pone.0238223. eCollection 2020.
Being delivered as a low birthweight (LBW) infant is a risk factor for elevated blood pressure and future problems with cardiovascular and cerebellar diseases. Although premature babies are reported to have low numbers of nephrons, some unclear questions remain about the mechanisms underlying elevated blood pressure in full-term LBW infants. We previously reported that glucocorticoids increased miR-449a expression, and increased miR-449a expression suppressed Crhr1 expression and caused negative glucocorticoid feedback. Therefore, we conducted this study to clarify the involvement of pituitary miR-449a in the increase in blood pressure caused by higher glucocorticoids in LBW rats. We generated a fetal low-carbohydrate and calorie-restricted model rat (60% of standard chow), and some individuals showed postnatal growth failure caused by growth hormone receptor expression. Using this model, we examined how a high-fat diet (lard-based 45kcal% fat)-induced mismatch between prenatal and postnatal environments could elevate blood pressure after growth. Although LBW rats fed standard chow had slightly higher blood pressure than control rats, their blood pressure was significantly higher than controls when exposed to a high-fat diet. Observation of glomeruli subjected to periodic acid methenamine silver (PAM) staining showed no difference in number or size. Aortic and cardiac angiotensin II receptor expression was altered with compensatory responses. Blood aldosterone levels were not different between control and LBW rats, but blood corticosterone levels were significantly higher in the latter with high-fat diet exposure. Administration of metyrapone, a steroid synthesis inhibitor, reduced blood pressure to levels comparable to controls. We showed that high-fat diet exposure causes impairment of the pituitary glucocorticoid negative feedback via miR-449a. These results clarify that LBW rats have increased blood pressure due to high glucocorticoid levels when they are exposed to a high-fat diet. These findings suggest a new therapeutic target for hypertension of LBW individuals.
作为低出生体重（LBW）婴儿出生是高血压和未来心血管和小脑疾病的风险因素。虽然早产儿的肾单位数量较少，但关于足月 LBW 婴儿血压升高的机制仍存在一些不清楚的问题。我们之前报道过糖皮质激素会增加 miR-449a 的表达，而增加 miR-449a 的表达会抑制 Crhr1 的表达并导致负性糖皮质激素反馈。因此，我们进行了这项研究，以阐明垂体 miR-449a 在 LBW 大鼠中由更高的糖皮质激素引起的血压升高中的作用。我们生成了一种胎儿低碳水化合物和热量限制模型大鼠（标准饲料的 60%），其中一些个体由于生长激素受体表达而表现出生后生长失败。使用该模型，我们研究了高脂肪饮食（基于猪油的 45kcal%脂肪）引起的产前和产后环境之间的不匹配如何在生长后升高血压。虽然喂食标准饲料的 LBW 大鼠的血压略高于对照大鼠，但当暴露于高脂肪饮食时，其血压明显高于对照大鼠。周期性酸-米氏银（PAM）染色观察肾小球显示数量或大小无差异。主动脉和心脏血管紧张素 II 受体表达发生改变，伴有代偿反应。对照大鼠和 LBW 大鼠的血液醛固酮水平没有差异，但高脂肪饮食暴露后后者的血液皮质醇水平显著升高。给予类固醇合成抑制剂美替拉酮可将血压降低至与对照相似的水平。我们表明，高脂肪饮食暴露通过 miR-449a 损害垂体糖皮质激素的负反馈。这些结果表明，LBW 大鼠在暴露于高脂肪饮食时，由于高水平的糖皮质激素，其血压升高。这些发现为 LBW 个体的高血压提供了一个新的治疗靶点。
