VITAMIN D DEFICIENCY, INSULIN RESISTANCE AND CARDIOVASCULAR DISEASE

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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.