VITAMIN D DEFICIENCY, INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

摘要 超过一半的2型糖尿病（T2 DM）患者会发展为高血压（HTN）， 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2型糖尿病患者的血管疾病，但对炎症反应的机制知之甚少。 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 在无并发症的T2 DM患者中，补充维生素B1已证明可降低血压，这表明可能对 这个人口。因此，本申请的目标是鉴定维生素D与细胞增殖的分子机制。 在T2 DM的情况下，HTN缺乏会促进HTN。我们的初步数据表明有巨噬细胞的小鼠- VDR特异性缺失（KODMAC）的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，和肾巨噬细胞浸润到 肾小球（JG）器，肾素产生的主要来源。来自KODMAC的腹膜巨噬细胞 或它们的培养基通过巨噬细胞分泌miR 106 b激活JG细胞肾素产生。这种影响被削弱了 由于缺乏巨噬细胞ER应激调节（C/EBP）同源蛋白（CHOP）。发现了类似的效果 用来自维生素D缺乏小鼠或来自维生素D缺乏T2 DM患者的巨噬细胞。因此我们 假设维生素D缺乏巨噬细胞增加2型糖尿病患者系统性肾素和高血压 通过增加miR-106 b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。为了检验这一假设，目标1将确定骨髓（BM） 从miR-106 b-/-或CHOP-/-移植到维生素D缺乏小鼠中改善HTN并降低全身性 肾素。在目标2中，我们将评估从Renin 1c-/-移植到维生素D缺乏小鼠中的BM是否改善 HTN和降低全身肾素。在目标3中，我们还将评估这些炎症机制的作用， 通过将血浆miR-106 b水平的变化与 维生素D补充后血压的变化（目标3a），并通过测试单核细胞或 来自患有HTN的维生素D缺乏型糖尿病患者的血清通过miR-106 b诱导JG细胞肾素分泌（Aim 3b）。这 该提案将确定维生素D缺乏症调节先天免疫系统的机制， 在2型糖尿病中诱导全身性肾素产生和HTN，从而为 这些普遍的疾病。

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.