Calcium-Independent And 1,25(OH)₂D₃-Dependent Regulation Of The Renin-Angiotension System In 1α-Hydroxylase Knockout Mice

To determine whether the cardiovascular effect of 1,25(OH)₂D₃ is dependent on calcium and/or hosphorus,after weaning mice with targeted deletion of the 25(OH)D 1a-hydroxylase and their wild-type littermates were fed a normal diet or a diet tO rescue the ambient serum calcium and phosphorus levels.After 3weeks on a normal diet,eight animals of each genotype received daily treatment of vehicle or 62.5ng 1,25(OH)₂D₃, intraperitoneally for four subsequent weeks.After 3 weeks on the "rescue diet",eight animals of each genotype received vehicle or 100mgkg^-1 captopril or 30mgkg^-1losartan.After four weeks the vehicle-treated knockout mice on a normal diet developed hypertension,cardiac hypertrophy and impaired cardiac function along with an up-regulation of the renin-angiotensin system in both renal and cardiac tissues.These results demonstrated that 1,25(OH)₂D₃ deficiency caused a hypertension, cardiac hypertrophy,cardiac systolic function imperfect and up-regulation of the RAS in mice.1α(OH)ase^-/-mice and their sex-matched wild-type littermates were fed a "rescue diet" containing 2%calcium,1.25%phosphorus,and 20%lactose for 4 weeks before analyses.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.These findings supported that the hypertension,cardiac hypertrophy,cardiac systolic function imperfect and the up-regulation of RAS occurred in 1,25(OH)₂D₃.deficient animals were a calcium-independent manner.Sex-matched wild-type and 1α(OH)ase^-/-mice on the normal diet received vehicle or 62.5ng 1,25(OH)₂D₃ for 4 weeks.As espected,1,25(OH)₂D₃ not only normalized serum calcium and phosphorus levels but also normalized blood pressure,cardiac structure-function and the renin-angiotensin system in both renal and cardiac tissues in mutant mice. Given that Angâ…¡is the central effector of the RAS,we assessed whether the abnormalities of cardiovascular system were rescued by the administration of the ACE inhibitor captopril or the Angâ…¡typeâ… receptor antagonist losartan in 1α(OH)ase^-/-mice.The 6-week-old, sex-matched wild-type and 1α(OH)ase^-/-mice on "rescue diet" received vehicle or 100mg /Kg captopril,or 30mg/Kg losartan,intragastrically daily for 4 subsequent weeks,the systolic blood pressure was measured, the cardiac structure,cardiac systolic function and the RAS parameters were examined.Results revealed that 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)₂D₃ plays a protective role in the cardiovascular system by repressing the renin-angiotensin system independent of extracellular calcium or phosphorus.