1,25-Dihydroxyvitamin D₃ is a negative endocrine regulator of the renin-angiotensin system. This study demonstrates that vitamin D receptor-null (VDR-null) mice exhibit increased renin expression and plasma angiotensin II (Ang II) levels, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis remain intact in these mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) synthesis increases renin expression, while injection of 1,25(OH)₂D₃ suppresses it. Vitamin D regulation of renin expression is independent of calcium metabolism and 1,25(OH)₂D₃ markedly suppresses renin transcription via a VDR-mediated mechanism in cell cultures. These findings indicate that 1,25(OH)₂D₃ is a novel negative endocrine regulator of the renin-angiotensin system. Its critical role in electrolyte, volume, and blood pressure homeostasis suggests that vitamin D analogs could help prevent or ameliorate hypertension. The study also shows that renin expression in VDR-null mice is not due to hypocalcemia or hyperparathyroidism but is a direct result of VDR inactivation. 1,25(OH)₂D₃ directly suppresses renin gene transcription in a VDR-mediated manner. These results establish vitamin D as a potent negative endocrine regulator of the renin-angiotensin system.1,25-Dihydroxyvitamin D₃ is a negative endocrine regulator of the renin-angiotensin system. This study demonstrates that vitamin D receptor-null (VDR-null) mice exhibit increased renin expression and plasma angiotensin II (Ang II) levels, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis remain intact in these mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) synthesis increases renin expression, while injection of 1,25(OH)₂D₃ suppresses it. Vitamin D regulation of renin expression is independent of calcium metabolism and 1,25(OH)₂D₃ markedly suppresses renin transcription via a VDR-mediated mechanism in cell cultures. These findings indicate that 1,25(OH)₂D₃ is a novel negative endocrine regulator of the renin-angiotensin system. Its critical role in electrolyte, volume, and blood pressure homeostasis suggests that vitamin D analogs could help prevent or ameliorate hypertension. The study also shows that renin expression in VDR-null mice is not due to hypocalcemia or hyperparathyroidism but is a direct result of VDR inactivation. 1,25(OH)₂D₃ directly suppresses renin gene transcription in a VDR-mediated manner. These results establish vitamin D as a potent negative endocrine regulator of the renin-angiotensin system.