title: Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and renal transcriptome to prevent prenatal NG-Nitro-L-arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring.
abstract: BACKGROUND
  Pregnancy is a critical time for fetal programming of hypertension. Nitric oxide deficiency during pregnancy causes hypertension in adult offspring.
  
  
  OBJECTIVE
  We examined whether maternal melatonin or N-acetylcysteine therapy can prevent NG-nitro-L-arginine-methyl ester-induced fetal programming of hypertension in adult offspring. Next, we aimed to identify potential gatekeeper pathways that contribute to NG-nitro-L-arginine-methyl ester -induced programmed hypertension using the next generation RNA sequencing technology.
  
  
  METHODS
  Pregnant Sprague-Dawley rats were assigned to 4 groups: control, NG-nitro-L-arginine-methyl ester, NG-nitro-L-arginine-methyl ester +melatonin, and NG-nitro-L-arginine-methyl ester+N-acetylcysteine. Pregnant rats received NG-nitro-L-arginine-methyl ester administration at 60 mg/kg/d subcutaneously during pregnancy alone, with additional 0.01% melatonin in drinking water, or with additional 1% N-acetylcysteine in drinking water during the entire pregnancy and lactation. Male offspring (n=8/group) were killed at 12 weeks of age.
  
  
  RESULTS
  NG-nitro-L-arginine-methyl ester exposure during pregnancy induced programmed hypertension in adult male offspring, which was prevented by maternal melatonin or N-acetylcysteine therapy. Protective effects of melatonin and N-acetylcysteine against NG-nitro-L-arginine-methyl ester-induced programmed hypertension were associated with an increase in hydrogen sulfide-generating enzymes and hydrogen sulfide synthesis in the kidneys. Nitric oxide inhibition by NG-nitro-L-arginine-methyl ester in pregnancy caused >2000 renal transcripts to be modified during nephrogenesis stage in 1-day-old offspring kidney. Among them, genes belong to the renin-angiotensin system, and arachidonic acid metabolism pathways were potentially involved in the NG-nitro-L-arginine-methyl ester-induced programmed hypertension. However, melatonin and N-acetylcysteine reprogrammed the renin-angiotensin system and arachidonic acid pathway differentially.
  
  
  CONCLUSIONS
  Our results indicated that antioxidant therapy, by melatonin or N-acetylcysteine, in pregnant rats with nitric oxide deficiency can prevent programmed hypertension in male adult offspring. Early intervention with specific antioxidants that target redox imbalance in pregnancy to reprogram hypertension may well allow us to reduce the future burden of hypertension. The roles of transcriptome changes that are induced by NG-nitro-L-arginine-methyl ester in the offspring kidney require further clarification.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, 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 Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chien-Te
authors.initials: CT
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: Julie Y H
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: chien_ning_hsu@hotmail.com.
authors.forename: Chien-Ning
authors.initials: CN
authors.lastname: Hsu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000187:drug effects / Q000502:physiology; D006862:Hydrogen Sulfide / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D019331:NG-Nitroarginine Methyl Ester; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D008550:Melatonin; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine; D006862:Hydrogen Sulfide
keywords: N-acetylcysteine; hydrogen sulfide; hypertension; melatonin; nitric oxide; oxidative stress