VITAMIN D DEFICIENCY, INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

摘要 超过一半的2型糖尿病(T2 DM)患者会患高血压(HTN)，高血压的发病率会增加一倍 他们患心血管疾病(CVD)的风险。尽管众所周知，胰岛素抵抗和慢性 炎症导致HTN并加速T2 DM患者的血管病变，目前对此知之甚少 这些危险因素促进HTN和CVD的机制。2型糖尿病患者维生素D缺乏症 几乎是非糖尿病患者的两倍，大多数评估维生素D的随机临床试验 在不复杂的T2 DM患者中，补充补充剂已经显示出血压的降低，这表明可能对 这群人。因此，这项应用的目标是确定维生素D 在T2 DM环境中，缺乏促进HTN的发生。我们的初步数据显示，有巨噬细胞的小鼠- VDR的特异性缺失(KODMAC)是高血压伴全身性肾素升高、 巨噬细胞肾素血管紧张素系统(RAS)在主动脉和肾脏的巨噬细胞渗入 肾小球旁(JG)器是肾素产生的主要来源。KODMAC来源的腹膜巨噬细胞 或其培养液通过巨噬细胞分泌miR106b激活JG细胞肾素的产生。这一效果被削弱了。 由于缺乏巨噬细胞内质网应激调节蛋白(C/EBP)同源蛋白(CHOP)。也发现了类似的影响 来自缺乏维生素D的小鼠或缺乏维生素D的2型糖尿病患者的巨噬细胞。因此，我们 假设维生素D缺乏的巨噬细胞增加了T2 DM患者的全身性肾素和高血压 通过增加miR-106b的分泌，刺激JG细胞的肾素分泌，和/或通过巨噬细胞 RAS依赖机制。为了验证这一假设，目标1将确定骨髓(BM) 从miR-106b-/-或chop-/-移植到维生素D缺乏的小鼠可改善HTN并降低系统性 肾素。在目标2中，我们将评估骨髓从肾素1c-/-移植到维生素D缺乏的小鼠是否有改善 HTN和降低全身性肾素。在目标3中，我们还将评估这些炎症机制的作用 血浆miR-106b水平变化与T2 DM和维生素D缺乏患者HTN的相关性 补充维生素D后血压的变化(目标3a)，并通过测试单核细胞或 维生素D缺乏性糖尿病伴HTN患者血清通过miR-106b(Aim 3b)诱导JG细胞肾素分泌。这 该提案将确定维生素D缺乏调节先天免疫系统的机制 诱导2型糖尿病全身性肾素生成和hTN，从而为2型糖尿病提供新的治疗靶点 这些无处不在的疾病。

ABSTRACT More than half of patients with type 2 diabetes mellitus (T2DM) develop hypertension (HTN), which doubles their risk for cardiovascular disease (CVD). Even though it is well known that insulin resistance and chronic inflammation lead to HTN and accelerate vascular disease in patients with T2DM, very little is known about the mechanisms by which these risk factors promote HTN and CVD. Vitamin D deficiency in patients with T2DM is almost twice that of non-diabetics, and most of the randomized clinical trials evaluating vitamin D supplementation in uncomplicated T2DM have demonstrated BP reductions, suggesting a possible effect in this population. Thus, the goal of this application is to identify the molecular mechanisms by which vitamin D deficiency promotes HTN in the setting of T2DM. Our preliminary data indicates that mice with macrophage- specific deletion of the VDR (KODMAC) were hypertensive with increased systemic renin, activation of the macrophage renin angiotensin system (RAS) in the aorta, and renal macrophage infiltration into the juxtaglomerular (JG) apparatus, the main source of renin production. Peritoneal macrophages from KODMAC or their media activated JG cell renin production via macrophage secretion of miR106b. This effect was blunted by lack of macrophage ER stress-regulated (C/EBP) homologous protein (CHOP). Similar effects were found with macrophages from vitamin D-deficient mice or from vitamin D-deficient patients with T2DM. Thus, we hypothesize that vitamin D-deficient macrophages increase systemic renin and hypertension in T2DM via increased secretion of miR-106b, stimulating renin secretion by JG cells, and/or via macrophage RAS-dependent mechanism. To test this hypothesis, Aim 1 will determine whether bone marrow (BM) transplant from miR-106b-/- or CHOP-/- into vitamin D-deficient mice improves HTN and decreases systemic renin. In Aim 2, we will evaluate whether BM transplant from Renin 1c-/- into vitamin D-deficient mice improves HTN and decreases systemic renin. In Aim 3, we will also assess the role of these inflammatory mechanisms of HTN in patients with T2DM and vitamin D deficiency by correlating changes in plasma miR-106b levels with changes in blood pressure after vitamin D supplementation (Aim 3a) and by testing whether monocytes or serum from vitamin D-deficient diabetics with HTN induce JG cell renin secretion via miR-106b (Aim 3b). This proposal will identify the mechanisms by which vitamin D deficiency regulates the innate immune system to induce systemic renin production and HTN in type 2 diabetes and thus, provide new therapeutic targets for these pervasive diseases.