title: Administration of exogenous 1,25(OH)2D3 normalizes overactivation of the central renin-angiotensin system in 1α(OH)ase knockout mice.
abstract: Previously, we reported that active vitamin D deficiency in mice causes secondary hypertension and cardiac dysfunction, but the underlying mechanism remains largely unknown. To clarify whether exogenous active vitamin D rescues hypertension by normalizing the altered central renin-angiotensin system (RAS) via an antioxidative stress mechanism, 1-alpha-hydroxylase [1α(OH)ase] knockout mice [1α(OH)ase(-/-)] and their wild-type littermates were fed a normal diet alone or with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a high-calcium, high-phosphorus "rescue" diet with or without antioxidant N-acetyl-l-cysteine (NAC) supplementation for 4 weeks. Compared with their wild-type littermates, 1α(OH)ase(-/-)mice had high mean arterial pressure, increased levels of renin, angiotensin II (Ang II), and Ang II type 1 receptor, and increased malondialdehyde levels, but decreased anti-peroxiredoxin I and IV proteins and the antioxidative genes glutathione reductase (Gsr) and glutathione peroxidase 4 (Gpx4) in the brain samples. Except Ang II type 1 receptor, these pathophysiological changes were rescued by exogenous 1,25(OH)2D3 or NAC plus rescue diet, but not by rescue diet alone. We conclude that 1,25(OH)2D3 normalizes the altered central RAS in 1α(OH)ase(-/-)mice, at least partially, through a central antioxidative mechanism.
authors.affiliation: Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China; Department of Human Anatomy, Kangda College, Lianyungang, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China. Electronic address: luqingzh@njmu.edu.cn.
authors.forename: Luqing
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Ding
authors.affiliation: Calcium Research Laboratory, McGill University Health Center and Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Department of Human Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000008:administration & dosage; D004032:Diet; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D010758:Phosphorus / Q000008:administration & dosage; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D044140:Receptor, Angiotensin, Type 1; D014815:Vitamins; D000804:Angiotensin II; D010758:Phosphorus; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D012083:Renin; D002117:Calcitriol; D002118:Calcium; D000111:Acetylcysteine
keywords: 1-Alpha-hydroxylase knockout; Central nervous system; Hypertension; Oxidative stress; Renin–angiotensin system; Vitamin D