Cardiovascular Effect of the Vitamin D Endocrine System.

描述(申请人提供)：越来越多的临床和实验证据支持维生素D内分泌系统在调节心血管功能中的重要作用。例如，维生素D疗法已被证明可以显著降低血液透析患者的心血管死亡风险。肾素-血管紧张素系统(RAS)在维持电解质、细胞外容量和血压动态平衡方面起着核心作用，RAS的过度激活可导致高血压、心肌肥厚和动脉粥样硬化等心血管问题。在过去的几年里，我们已经获得了大量的证据表明，维生素D通过抑制肾素的生物合成来调节RAS。我们发现，在小鼠中，维生素D信号的中断导致RAS的激活，导致高血压和心肌肥大，1，25-二羟基维生素D3通过VDR依赖的机制直接抑制肾素基因的转录。在这一应用中，我们将通过提出三个具体的目标来继续探讨维生素D对RAS的生理和药理作用。第一个目的是通过转基因方法进一步明确维生素D和甲状旁腺激素(PTH)在体内调节RAS的作用。我们将研究在产生肾素的JG细胞中过度表达人(H)VDR的转基因(TG)小鼠，以及仅在JG细胞中表达hVDR转基因(VDRKO-hVDR)的VDR基因敲除(KO)小鼠。对野生型、VDRKO、TG-hVDR和VDRKO-hVDR小鼠的平行分析将使我们进一步阐明维生素D和甲状旁腺素在体内调节肾素基因表达的作用。第二个目的是阐明维生素D调节肾素基因表达的分子机制。在我们现有证据的基础上，我们将重点探讨两个间接机制：一是维生素D通过刺激其他转录抑制因子抑制肾素的表达；二是VDR通过肾素基因启动子中的环状AMP反应元件(CRE)与其他调节肾素转录的因素发生物理相互作用。第三个目标是探索维生素D类似物作为肾素抑制剂和抗高血压药物的潜力。我们发现维生素D是RAS的一种有效的负性内分泌调节因子，这为探索维生素D类似物作为肾素抑制剂用于治疗的潜力提供了分子基础。我们已经确定了一组低钙维生素D类似物，它们可以有效地抑制细胞培养和小鼠体内肾素的生物合成和血浆肾素活性。我们将在Goldblatt高血压大鼠和自发性高血压大鼠等高肾素高血压动物模型上进一步测试这些类似物减少肾素产生和降低血压的效果。这些研究将进一步加深我们对维生素D内分泌系统的新生理学及其在调节RAS和心血管系统中的药理学应用的理解。

DESCRIPTION (provided by applicant): Accumulating clinical and experimental evidence has supported an important role of the vitamin D endocrine system in the regulation of cardiovascular functions. For instance, vitamin D therapy has been shown to significantly reduce the risk of cardiovascular death among hemodialysis patients. The renin-angiotensin system (RAS) plays a central role in the maintenance of electrolyte, extracellular volume and blood pressure homeostasis; over-activation of the RAS has been well known to cause cardiovascular problems such as hypertension, cardiac hypertrophy and atherosclerosis. In the past years we had obtained a great deal of evidence demonstrating that vitamin D regulates the RAS by suppressing renin biosynthesis. We found that disruption of the vitamin D signaling in mice results in activation of the RAS, leading to high blood pressure and cardiac hypertrophy, and that 1,25-dihydroxyvitamin D3 directly suppresses renin gene transcription by a VDR-dependent mechanism. In this application, we will continue to explore the physiological and pharmacological effects of vitamin D on the RAS by proposing three Specific Aims. The first Aim is to further define the role of vitamin D and parathyroid hormone (PTH) in the regulation of the RAS in vivo by transgenic approach. We will study transgenic (Tg) mice overexpressing human (h) VDR in renin-producing JG cells as well as VDR knockout (KO) mice that express the hVDR transgene (VDRKO-hVDR) only in JG cells. Parallel analyses of wild-type, VDRKO, Tg-hVDR and VDRKO-hVDR mice will allow us to further clarify the in vivo role of vitamin D and PTH in the regulation of renin gene expression. The second Aim is to elucidate the molecular mechanism underlying the regulation of renin gene expression by vitamin D. Based on our existing evidence, we will focus on exploring two indirect mechanisms: one is that vitamin D suppresses renin expression via stimulating other transcriptional represser, and the other is that VDR physically interacts with other factors that regulate renin transcription via cyclic AMP response element (CRE) in renin gene promoter. The third Aim is to explore the potential of vitamin D analogs as renin inhibitors and anti- hypertensive agents. Our discovery of vitamin D as a potent negative endocrine regulator of the RAS provides a molecular basis to explore the potential of vitamin D analogs as renin inhibitors for therapeutic purposes. We have identified a group of low calcemic vitamin D analogs that can effectively suppress renin biosynthesis and plasma renin activity in cell cultures and in mice. We will further test the efficacy of these analogs to reduce renin production and to lower blood pressure in high-renin hypertensive animal models such as the Goldblatt hypertensive rats and spontaneously hypertensive rats. These studies will further enhance our understanding of the novel physiology of the vitamin D endocrine system and its pharmacological applications in the regulation of the RAS and cardiovascular system.