Loss of Vitamin D Receptor Produces Polyuria by Increasing Thirst

Abstract

Vitamin D receptor (VDR)-null mice develop polyuria, but the underlying mechanism remains unknown. In this study, we investigated the relationship between vitamin D and homeostasis of water and electrolytes. VDR-null mice had polyuria, but the urine osmolarity was normal as a result of high salt excretion. The urinary responses to water restriction and to vasopressin were similar between wild-type and VDR-null mice, suggesting intact fluid-handling capacity in VDR-null mice. Compared with wild-type mice, however, renin and angiotensin II were dramatically upregulated in the kidney and brain of VDR-null mice, leading to a marked increase in water intake and salt appetite. Angiotensin II-mediated upregulation of intestinal NHE3 expression partially explained the increased salt absorption and excretion in VDR-null mice. In the brain of VDR-null mice, expression of c-Fos, which is known to associate with increased water intake, was increased in the hypothalamic paraventricular nucleus and the subfornical organ. Treatment with an angiotensin II type 1 receptor antagonist normalized water intake, urinary volume, and c-Fos expression in VDR-null mice. Furthermore, despite a salt-deficient diet to reduce intestinal salt absorption, VDR-null mice still maintained the increased water intake and urinary output. Together, these data indicate that the polyuria observed in VDR-null mice is not caused by impaired renal fluid handling or increased intestinal salt absorption but rather is the result of increased water intake induced by the increase in systemic and brain angiotensin II.

Vitamin D and the Renin-Angiotensin System

“…As expected, plasma and urinary aldosterone levels are also markedly elevated in VDR knockout mice [71]. Moreover, renin expression in the brain is also up-regulated in VDR-null mice, leading to activation of the local RAS in the brain, which is mostly responsible for the overdrinking and polyuric phenotypes seen in the mutant mice [72].…”

Therapeutic Effects of Vitamin D Analogs on Cardiac Hypertrophy in Spontaneously Hypertensive Rats

“…38 Here our immunostaining data showed that renin is highly induced by losartan in the blood vessel walls in the left ventricle, and this finding is consistent with our previous report that renin expression was detected in the vasculatures in mouse brain. 39 The exact role of endothelial renin deserves further investigations.…”

Nocturnal Enuresis in Children and Adolescent with Sickle cell Anemia

“…In another study, using similar mice, reduction of renin-angiotensin activity in paraventricular nucleus with inhibition of thirst was achieved following vitamin D analogs injection. The authors concluded that polydipsia and polyuria may be caused by a lack of vitamin D [150]. Nocturnal polyuria had been reported in normal children [152,153] and children with SCA who had NE and was considered a pathogenic factor [18,41,51,52].…”

“…Vitamin D receptor knockout mice that had normal renal function were observed to develop polyuria, as a result of increased water intake [150]. The latter was due to renin up regulation leading to an increased production of angiotensin II [151].…”