title: Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension.
abstract: Glucocorticoids are administered to premature infants to accelerate pulmonary maturation. In experimental model, prenatal dexamethasone (DEX) results in reduced nephron number and adulthood hypertension. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), can cause oxidative stress and is involved in the development of hypertension. L-citrulline can be converted to l-arginine (the substrate for NOS) in the body. Thus we intended to determine if maternal L-citrulline therapy can prevent prenatal DEX-induced programmed hypertension by restoration ADMA/nitric oxide (NO) balance, alterations of renin-angiotensin system (RAS) and sodium transporters, and epigenetic regulation by histone deacetylases (HDACs). Male offspring were assigned to four groups: control, pregnancy rats received intraperitoneal DEX (0.2 mg/kg body weight) daily on gestational days 15 and 16 (DEX), pregnancy rats received 0.25% L-citrulline in drinking water during the entire pregnancy and lactation period (CIT), and DEX + CIT. We found DEX group developed hypertension at 16 weeks of age, which was prevented by maternal L-citrulline therapy. Prenatal DEX exposure increased plasma ADMA concentrations and reduced renal NO production. However, L-citrulline reduced plasma ADMA level and increased renal level of NO in DEX + CIT group. Next, prenatal DEX-induced programmed hypertension is related to increased mRNA expression of angiotensin and angiotensin II type 1 receptor, and class I HDACs in the kidney. Prenatal DEX exposure increased renal protein abundance of Na(+)/Cl(-) cotransporter (NCC), which was prevented by L-citrulline therapy. The beneficial effects of L-citrulline therapy include restoration of ADMA/NO balance and alteration of NCC, to prevent the prenatal DEX-induced programmed hypertension.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine , Kaohsiung , Taiwan.
authors.forename: Y L
authors.initials: YL
authors.lastname: Tain
authors.forename: J M
authors.initials: JM
authors.lastname: Sheen
authors.forename: C C
authors.initials: CC
authors.lastname: Chen
authors.forename: H R
authors.initials: HR
authors.lastname: Yu
authors.forename: M M
authors.initials: MM
authors.lastname: Tiao
authors.forename: H C
authors.initials: HC
authors.lastname: Kuo
authors.forename: L T
authors.initials: LT
authors.lastname: Huang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002956:Citrulline / Q000008:administration & dosage / Q000627:therapeutic use*; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced*; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; D003907:Dexamethasone