Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia.
PLoS One. 2021 Mar 18;16(3):e0248854. doi: 10.1371/journal.pone.0248854. eCollection 2021.
Maternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring.
C57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32.
In week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring.
Gestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption.
母体高脂肪饮食（HFD）会促进后代慢性肾脏病（CKD）的发生。这符合胎儿编程理论，即子宫内发生的不利条件使后代易患生命后期的慢性疾病。DNA 甲基化被认为是胎儿编程发生的关键机制，并与 CKD 的进展有关。DNA 去甲基化药物可能会通过母体肥胖中断 CKD 的胎儿编程。肼屈嗪是一种抗高血压药物，低剂量即可使 DNA 去甲基化，而不会降低血压。我们使用了母体肥胖的小鼠模型来确定母体在妊娠期给予低剂量肼屈嗪是否可以预防后代的 CKD。
C57BL/6 母鼠在交配前 6 周开始接受 HFD 或标准饮食，并在妊娠期每周接受 3 次皮下注射肼屈嗪（5mg/kg）或生理盐水。雄性后代断奶后给予标准饮食，并在出生后第 9 或 32 周处死。在第 9 和 32 周时，测量后代的生物计量和代谢参数、肾脏总 DNA 甲基化、肾脏结构和功能变化以及纤维化、氧化应激和炎症标志物。
在第 9 周时，母体 HFD 摄入并未显著改变后代的人体测量学或代谢参数，或肾脏总 DNA 甲基化。第 32 周时，肥胖组后代的肾脏总 DNA 甲基化增加，同时出现白蛋白尿、肾小球硬化、肾纤维化和氧化应激。在妊娠期给予肥胖母亲低剂量肼屈嗪可降低第 32 周时后代的肾脏总 DNA 甲基化和肾纤维化标志物。
妊娠期肼屈嗪降低了肥胖母亲后代的肾脏总 DNA 甲基化，并减轻了母体肥胖引起的肾脏纤维化。这些数据支持使用低剂量肼屈嗪作为去甲基化剂，以预防因母体 HFD 摄入而导致的后代 CKD 的发生。
