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.

Public Health Relevance

It is well-recognized that chronic inflammation integrates insulin resistance with hypertension and cardiovascular complications, but the mechanisms are undefined. We found that cell-specific deletion of the macrophage vitamin D receptor in mice is sufficient to cause renin-dependent hypertension, which corrects with bone marrow (BM) transplantation of cells with intact VDR. This study will determine whether macrophage RAS activation and/or miR106b secretion are critical mechanism by which vitamin D-deficiency increased systemic renin and induce hypertension in a mouse model of insulin resistance and in patients with type 2 diabetes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Kirby, Ruth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Oh, Jisu; Riek, Amy E; Zhang, Rong M et al. (2018) Deletion of JNK2 prevents vitamin-D-deficiency-induced hypertension and atherosclerosis in mice. J Steroid Biochem Mol Biol 177:179-186
Riek, Amy E; Oh, Jisu; Darwech, Isra et al. (2018) Vitamin D3 supplementation decreases a unique circulating monocyte cholesterol pool in patients with type 2 diabetes. J Steroid Biochem Mol Biol 177:187-192
Nicol, Ginger E; de Las Fuentes, Lisa; Riek, Amy E et al. (2015) Adiposity and Cardiometabolic Risk in Children With and Without Antipsychotic Drug Treatment. J Clin Endocrinol Metab 100:3418-26
Oh, Jisu; Riek, Amy E; Darwech, Isra et al. (2015) Deletion of macrophage Vitamin D receptor promotes insulin resistance and monocyte cholesterol transport to accelerate atherosclerosis in mice. Cell Rep 10:1872-86
Riek, Amy E; Oh, Jisu; Darwech, Isra et al. (2014) 25(OH) vitamin D suppresses macrophage adhesion and migration by downregulation of ER stress and scavenger receptor A1 in type 2 diabetes. J Steroid Biochem Mol Biol 144 Pt A:172-9
Riek, Amy E; Oh, Jisu; Bernal-Mizrachi, Carlos (2013) 1,25(OH)2 vitamin D suppresses macrophage migration and reverses atherogenic cholesterol metabolism in type 2 diabetic patients. J Steroid Biochem Mol Biol 136:309-12
Weng, Sherry; Sprague, Jennifer E; Oh, Jisu et al. (2013) Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice. PLoS One 8:e54625
Oh, Jisu; Riek, Amy E; Weng, Sherry et al. (2012) Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287:11629-41
Riek, Amy E; Oh, Jisu; Sprague, Jennifer E et al. (2012) Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem 287:38482-94
Mulligan, Megan L; Felton, Shaili K; Riek, Amy E et al. (2010) Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol 202:429.e1-9

Showing the most recent 10 out of 12 publications