The study investigates the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in regulating the renin-angiotensin system, which plays a crucial role in maintaining blood pressure, electrolyte, and volume homeostasis. The researchers found that vitamin D receptor-null (VDR-null) mice exhibit increased renin expression and plasma angiotensin II production, leading to hypertension, cardiac hypertrophy, and increased water intake. Despite the elevated renin levels, the salt-and volume-sensing mechanisms that control renin synthesis remain intact in these mice. In wild-type mice, inhibition of 1,25(OH)2D3 synthesis also increased renin expression, while 1,25(OH)2D3 injection suppressed renin expression. The study demonstrates that vitamin D regulation of renin expression is independent of calcium metabolism and occurs through a VDR-mediated mechanism. Specifically, 1,25(OH)2D3 directly suppresses renin gene transcription in cell cultures. These findings suggest that 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system and that vitamin D analogues could potentially help prevent or treat hypertension.The study investigates the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in regulating the renin-angiotensin system, which plays a crucial role in maintaining blood pressure, electrolyte, and volume homeostasis. The researchers found that vitamin D receptor-null (VDR-null) mice exhibit increased renin expression and plasma angiotensin II production, leading to hypertension, cardiac hypertrophy, and increased water intake. Despite the elevated renin levels, the salt-and volume-sensing mechanisms that control renin synthesis remain intact in these mice. In wild-type mice, inhibition of 1,25(OH)2D3 synthesis also increased renin expression, while 1,25(OH)2D3 injection suppressed renin expression. The study demonstrates that vitamin D regulation of renin expression is independent of calcium metabolism and occurs through a VDR-mediated mechanism. Specifically, 1,25(OH)2D3 directly suppresses renin gene transcription in cell cultures. These findings suggest that 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system and that vitamin D analogues could potentially help prevent or treat hypertension.