Effect of Angiotensin II Type I Receptor Antagonist and Angiotensin-Converting Enzyme Inhibitor on Vitamin D Receptor Null Mice

Running title: Effect of ACE and AT 1 blockers on VDR null mice Abstract We have recently shown that vitamin D receptor (VDR) inactivation results in deregulated stimulation of the renin-angiotensin system (RAS). To address further the relationship between RAS activation and the abnormalities in electrolyte and volume homeostasis, we studied the effect of AT 1 receptor antagonist losartan and angiotensin-converting enzyme inhibitor captopril on VDR-null mice. Treatment with losartan or captopril normalized the water intake and urine excretion of VDR-null mice. However, the increase in salt excretion in VDR-null mice was not affected by either drug, suggesting that this abnormality is independent of the RAS. Northern blot and immunohistochemical analyses revealed that both drugs caused a drastic stimulation of renin expression in both wild-type and VDR-null mice, but renin expression in the treated VDR-null mice remained much higher than in the treated wild-type mice, suggesting that the angiotensin (Ang) II feedback mechanism remains intact in the mutant mice. These data firmly established a causative relationship between RAS over-stimulation and the abnormal volume homeostasis in VDR-null mice, and demonstrated that vitamin D repression of renin expression is independent of the Ang II feedback regulation in vivo.