title: Melatonin prevents maternal fructose intake-induced programmed hypertension in the offspring: roles of nitric oxide and arachidonic acid metabolites.
abstract: Fructose intake has increased globally and is linked to hypertension. Melatonin was reported to prevent hypertension development. In this study, we examined whether maternal high fructose (HF) intake causes programmed hypertension and whether melatonin therapy confers protection against the process, with a focus on the link to epigenetic changes in the kidney using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with HF (60% diet by weight) alone or with additional 0.01% melatonin in drinking water during the whole period of pregnancy and lactation. Male offspring were assigned to four groups: control, HF, control + melatonin (M), and HF + M. Maternal HF caused increases in blood pressure (BP) in the 12-wk-old offspring. Melatonin therapy blunted the HF-induced programmed hypertension and increased nitric oxide (NO) level in the kidney. The identified differential expressed gene (DEGs) that are related to regulation of BP included Ephx2, Col1a2, Gucy1a3, Npr3, Aqp2, Hba-a2, and Ptgs1. Of which, melatonin therapy inhibited expression and activity of soluble epoxide hydrolase (SEH, Ephx2 gene encoding protein). In addition, we found genes in arachidonic acid metabolism were potentially involved in the HF-induced programmed hypertension and were affected by melatonin therapy. Together, our data suggest that the beneficial effects of melatonin are attributed to its ability to increase NO level in the kidney, epigenetic regulation of genes related to BP control, and inhibition of SEH expression. The roles of DEGs by the NGS in long-term epigenetic changes in the adult offspring kidney require further clarification.
authors.affiliation: Department of Pediatrics, College of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, College of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, Kaohsiung, Taiwan.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Kay L H
authors.initials: KL
authors.lastname: Wu
authors.forename: Wei-Chia
authors.initials: WC
authors.lastname: Lee
authors.forename: Julie Y H
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005632:Fructose / Q000009:adverse effects*; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy*; D008550:Melatonin / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016718:Arachidonic Acid; D005632:Fructose; D009569:Nitric Oxide; D008550:Melatonin
keywords: arachidonic acid; asymmetric dimethylarginine; fructose; hypertension; melatonin; next-generation sequencing; nitric oxide; renin-angiotensin system