title: Targeting arachidonic acid pathway to prevent programmed hypertension in maternal fructose-fed male adult rat offspring.
abstract: Hypertension can be programmed in response to nutritional insults in early life. Maternal high-fructose (HF) intake induced programmed hypertension in adult male offspring, which is associated with renal programming and arachidonic acid metabolism pathway. We examined whether early treatment with a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-Deoxy-Δ12,14-prostagandin J2(15dPGJ2) can prevent HF-induced programmed hypertension. Pregnant Sprague Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) during the whole period of pregnancy and lactation. Four groups of male offspring were studied: control, HF, HF+AUDA and HF+15dPGJ2.In HF+AUDA group, mother rats received AUDA 25 mg/L in drinking water during lactation. In the HF+15dPGJ2group, male offspring received 15dPGJ21.5 mg/kg body weight by subcutaneous injection once daily for 1 week after birth. Rats were sacrificed at 12 weeks of age. Maternal HF-induced programmed hypertension is associated with increased renal protein level of SEH and oxidative stress, which early AUDA therapy prevents. Comparison of AUDA and 15dPGJ2treatments demonstrated that AUDA was more effective in preventing HF-induced programmed hypertension. AUDA therapy increases angiotensin converting enzyme-2 (ACE2) protein levels and PGE2levels in adult offspring kidney exposed to maternal HF. 15dPGJ2therapy increases plasma asymmetric dimethylarginine (ADMA) levels and decreases L-arginine-to-ADMA ratio. Better understanding of the impact of arachidonic acid pathway, especially inhibition of SEH, on renal programming may aid in developing reprogramming strategy to prevent programmed hypertension in children exposed to antenatal HF intake.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
authors.affiliation: Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taiwan.
authors.forename: Wei-Chia
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Kay L H
authors.initials: KLH
authors.lastname: Wu
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.affiliation: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan. Electronic address: jchan@adm.cgmh.org.tw.
authors.forename: Julie Y H
authors.initials: JYH
authors.lastname: Chan
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000070601:Diet, Carbohydrate Loading / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004794:Enzyme Repression / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005632:Fructose / Q000009:adverse effects; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007279:Injections, Subcutaneous; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007774:Lactation; D007850:Lauric Acids / Q000627:therapeutic use*; D054834:Lipocalins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000378:metabolism; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; C477819:15-deoxyprostaglandin J2; D000959:Antihypertensive Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D054834:Lipocalins; D005632:Fructose; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D004851:Epoxide Hydrolases; C529022:EPHX2 protein, rat; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D000218:Adamantane; D015230:Prostaglandin D2
keywords: Arachidonic acid; Developmental programming; Fructose; Hypertension; Nitric oxide; Renin–Angiotensin system; Soluble epoxide hydrolase