Tain You-Lin, Sheen Jiunn-Ming, Yu Hong-Ren, Chen Chih-Cheng, Tiao Mao-Meng, Hsu Chien-Ning, Lin Yu-Ju, Kuo Kuang-Che, Huang Li-Tung
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Kaohsiung, Taiwan ; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Kaohsiung, Taiwan.
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine Kaohsiung, Taiwan.
Front Physiol. 2015 Dec 11;6:377. doi: 10.3389/fphys.2015.00377. eCollection 2015.
Prenatal dexamethasone (DEX) exposure and high-fat (HF) intake are linked to hypertension. We examined whether maternal melatonin therapy prevents programmed hypertension synergistically induced by prenatal DEX plus postnatal HF in adult offspring. We also examined whether DEX and melatonin causes renal programming using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received intraperitoneal dexamethasone (0.1 mg/kg) or vehicle from gestational day 16 to 22. In the melatonin-treatment groups (M), rats received 0.01% melatonin in drinking water during their entire pregnancy and lactation. Male offspring were assigned to five groups: control, DEX, HF, DEX+HF, and DEX+HF+M. Male offspring in the HF group were fed a HF diet from weaning to 4 months of age. Prenatal DEX and postnatal HF diet synergistically induced programmed hypertension in adult offspring, which melatonin prevented. Maternal melatonin treatment modified over 3000 renal transcripts in the developing offspring kidney. Our NGS data indicate that PPAR signaling and fatty acid metabolism are two significantly regulated pathways. In addition, maternal melatonin therapy elicits longstanding alterations on renal programming, including regulation of the melatonin signaling pathway and upregulation of Agtr1b and Mas1 expression in the renin-angiotensin system (RAS), to protect male offspring against programmed hypertension. Postnatal HF aggravates prenatal DEX induced programmed hypertension in adult offspring, which melatonin prevented. The protective effects of melatonin on programmed hypertension is associated with regulation of the RAS and melatonin receptors. The long-term effects of maternal melatonin therapy on renal transcriptome require further clarification.
产前地塞米松（DEX）暴露和高脂（HF）摄入与高血压有关。我们研究了母体褪黑素治疗是否能预防成年后代中由产前DEX加产后HF协同诱导的程序性高血压。我们还使用下一代RNA测序（NGS）技术研究了DEX和褪黑素是否会导致肾脏编程。怀孕的Sprague-Dawley大鼠在妊娠第16天至22天接受腹腔注射地塞米松（0.1 mg/kg）或赋形剂。在褪黑素治疗组（M）中，大鼠在整个怀孕和哺乳期饮用含0.01%褪黑素的水。雄性后代被分为五组：对照组、DEX组、HF组、DEX+HF组和DEX+HF+M组。HF组的雄性后代从断奶到4个月大时喂食高脂饮食。产前DEX和产后HF饮食协同诱导成年后代出现程序性高血压，而褪黑素可预防这种情况。母体褪黑素治疗改变了发育中后代肾脏中超过3000种肾转录本。我们的NGS数据表明，PPAR信号通路和脂肪酸代谢是两个显著受调控的途径。此外，母体褪黑素治疗会对肾脏编程产生长期改变，包括调节褪黑素信号通路以及上调肾素-血管紧张素系统（RAS）中Agtr1b和Mas1的表达，以保护雄性后代免受程序性高血压的影响。产后HF会加重产前DEX诱导的成年后代程序性高血压，而褪黑素可预防这种情况。褪黑素对程序性高血压的保护作用与RAS和褪黑素受体的调节有关。母体褪黑素治疗对肾脏转录组的长期影响需要进一步阐明。
