Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice.
To determine whether the cardiovascular effect of 1,25(OH)(2)D is dependent on calcium and/or phosphorus, mice with targeted deletion of the 25(OH)D 1alpha-hydroxylase and their wild-type littermates were fed a normal diet or a diet to rescue the ambient serum calcium and phosphorus levels. Mice on the normal diet were treated daily with vehicle or 1,25(OH)(2)D(3) while mice on the rescue diet received vehicle, captopril or losartan. After four weeks the vehicle-treated knockout mice developed hypertension, cardiac hypertrophy and impaired cardiac function along with an up-regulation of the renin-angiotensin system in both renal and cardiac tissues. Although the serum calcium and phosphorus levels were normalized in knockout mice on the rescue diet, abnormalities in blood pressure, cardiac structure-function and the renin-angiotensin system remained. In contrast, 1,25(OH)(2)D(3) not only normalized serum calcium and phosphorus levels but also normalized blood pressure, cardiac structure-function and the renin-angiotensin system. Treatment of the knockout mice with either captopril or losartan normalized blood pressure and cardiac structure and function although renin expression remained elevated. This study shows that 1,25(OH)2D plays a protective role in the cardiovascular system by repressing the renin-angiotensin system independent of extracellular calcium or phosphorus.
Zhou
Chunlei
C
The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, PR of China.
Lu
Fengxiang
F
Cao
Kejiang
K
Xu
Di
D
Goltzman
David
D
Miao
Dengshun
D
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002216:Captopril / Q000008:administration & dosage; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control*; D017353:Gene Deletion; D018390:Gene Targeting; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control*; D019808:Losartan / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010758:Phosphorus / Q000097:blood / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism
D000959:Antihypertensive Agents; D014807:Vitamin D; D010758:Phosphorus; C097949:1,25-dihydroxyvitamin D; D002216:Captopril; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D019808:Losartan; D002118:Calcium