IntroductionThe renin-angiotensin system is a regulatory cascade that plays an essential role in the regulation of blood pressure, electrolyte, and volume homeostasis. The first and rate-limiting component of this cascade is renin, a protease synthesized and secreted predominantly by the juxtaglomerular (JG) apparatus in the nephron. Renin cleaves angiotensin I (Ang I) from liver-derived angiotensinogen, which is then converted to Ang II by the angiotensin-converting enzyme. Ang II, through binding to its receptors, exerts diverse actions that affect the electrolyte, volume, and blood pressure homeostasis (1). Inappropriate stimulation of the renin-angiotensin system has been associated with hypertension, heart attack, and stroke.The renin-producing granulated cells are mainly located in the afferent glomerular arterioles in the kidney (2). It is well established that renin secretion is regulated by renal perfusion pressure, renal sympathetic nerve activity, and tubular sodium load (1, 2). Renin secretion is stimulated by factors such as prostaglandins, NO, and adrenomedullin, and inhibited by other factors, including Ang II (feedback), endothelin, vasopressin, and adenosine (1, 2). Stimulation of renin secretion is often mediated by an increase in intracellular cAMP and is accompanied by increases in renin gene transcription (3). In the renin gene promoter, several cAMP response elements have been identified. Recently, steroid hormone receptors LXRα and RAR/RXR complex, transcriptional factors CREB/CREM and USF1/USF2, and HOX gene family members have been found to be involved in the activation of murine renin gene transcription (4-7).Vitamin D is a primary regulator of calcium homeostasis. Genetic inactivation of either the vitamin D receptor (VDR), a member of the nuclear receptor superfamily that mediates the action of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], or 25-hydroxyvitamin D 3 1α-hydroxylase, the rate-limiting enzyme for the biosynthesis of 1,25(OH) 2 D 3 , results in impaired calcium homeostasis, leading to hypocalcemia, secondary hyperparathyroidism, and rickets (8-11). However, the wide tissue distribution of VDR suggests that the vitamin D endocrine system has additional physiological functions beyond calcium homeostasis. Indeed, vitamin D and VDR have been shown to play important roles in the immune system, cardiovascular system, reproductive system, and hair growth. Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and ...

Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR). The VDR is expressed in many tissues, including several tissues not thought to play a role in mineral metabolism. Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopecia, which is not a feature of vitamin D deficiency, is seen in some kindreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite known expression of the VDR in fetal life, homozygous mice are phenotypically normal at birth and demonstrate normal survival at least until 6 months. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise. Hyperparathyroidism is accompanied by an increase in the size of the parathyroid gland as well as an increase in PTH mRNA levels. Rickets and osteomalacia are seen by day 35; however, as early as day 15, there is an expansion in the zone of hypertrophic chondrocytes in the growth plate. In contrast to animals made vitamin D deficient by dietary means, and like some patients with VDDR II, these mice develop progressive alopecia from the age of 4 weeks.1,25-Dihydroxyvitamin D is the major steroid hormone that plays a role in mineral ion homeostasis. Its actions are thought to be mediated by a nuclear receptor, the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor and interacts with specific DNA sequences on target genes. The VDR is evolutionarily well conserved and is expressed early in development in amphibians (1), mammals (2), and birds (3, 4). As well as being expressed in the intestine, the skeleton, and the parathyroid glands, the VDR is found in several tissues not thought to play a role in mineral ion homeostasis (5). Its precise functions in these tissues, as well as its developmental role, remain unclear.Insights into the physiological actions of 1,25-dihydroxyvitamin D have been obtained from studies in vitamin Ddeficient animals (6-10) as well as in humans with VDR mutations (11,12). These investigations have demonstrated that 1,25-dihydroxyvitamin D plays an important role in intestinal calcium absorption and that animals lacking the active hormone or its nuclear receptor develop hypocalcemia, rickets, osteomalacia, and hyperparathyroidism. Although skin changes similar to psoriasis have been observed in vitamin D-deficient rats (13), the alopecia observed in some kindreds with mutant VDRs has not been observed in vitamin D deficiency.We have generated an animal model of vitamin Ddependent rickets type II (VDDR II) by targeted ablation of DNA encoding the second zinc finger of the DNA-binding domain of the VDR. The resultant animals are phenotypically normal at birth; however, they develop hypocalcemia, hyperparathyroidism, and alopecia within the first month of life. MATERIALS AND METHODSGenera...