Independent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the renin-angiotensin system The Ludwigshafen Risk and Cardiovascular Health (LURIC) study
Antihypertensive and tissue-protective properties of vitamin D metabolites are increasingly attributed to the inhibition of renin synthesis by 1,25-dihydroxyvitamin D [1,25(OH)2D] in the kidney.
We aimed to document a potential association between 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D and the circulating renin-angiotensin system (RAS) in a large cohort of patients referred (n=3316) to coronary angiography.
Of the 3316 subjects, 3296 (median age: 63.5 (56.3-70.6)years; 30.2% women) had a baseline measurement of 25(OH)D [median: 15.6(10.1-23.0)microg/L)], 1,25(OH)2D [median: 33.2(25.2-42.9)pg/mL], plasma renin concentration [PRC; median: 11.4(6.0-24.6)pg/mL] and angiotensin 2 [median: 20.0(12.0-35.0)ng/L]. Multivariate adjusted ANCOVA showed a steady increase of PRC values across declining deciles of 25(OH)D and 1,25(OH)2D values (P=0.013 and P=0.045), respectively. Additionally, mean angiotensin 2 values increased significantly across decreasing 25(OH)D and 1,25(OH)2D values (P=0.020 and P=0.024, respectively). In contrast, multivariate adjusted ANCOVA revealed no significant associations between aldosterone, aldosterone-to-renin ratio and 25(OH)D/1,25(OH)2D values. In multivariate stepwise regression analyses both, 25(OH)D and 1,25(OH)2D emerged as independent predictors of plasma renin and angiotensin 2 concentrations.
Our data showed for the first time in humans that both, lower 25(OH)D and 1,25(OH)2D values are independently related to an upregulated circulating RAS.
Available from: Kyung-Soon Hong
- "In many observational studies, vitamin D deficiency was strongly associated with cardiometabolic risk factors such as endothelial dysfunction  and diabetes [1,2]. Vitamin D was suggested to negatively regulate the renin-angiotensin system [33,34] and inhibit smooth muscle cell proliferation and macrophage activation [35,36]. "
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Recent epidemiological studies revealed a striking inverse relationship between vitamin D levels, glucose intolerance/insulin resistance (IR), and cardiovascular disease. However, few interventional studies have evaluated the effect of vitamin D supplementation on cardiovascular risk, such as IR and arterial stiffness, in diabetes. We investigated the role of vitamin D supplementation on cardiovascular risk in type 2 diabetes patients, including metabolic parameters, IR, and arterial stiffness.
We enrolled patients who were taking antidiabetic medications or managed their diabetes using lifestyle changes. We excluded patients who were taking vitamin D or calcium supplements. We randomized participants into the vitamin D group (cholecalciferol 2,000 IU/day + calcium 200 mg/day, n = 40) or the placebo group (calcium 200 mg/day, n = 41). We compared their IR (homeostasis model of assessment [HOMA]-IR) and arterial stiffness (brachial-ankle pulse wave velocity and radial augmentation index) before and after 24 weeks of intervention.
The baseline characteristics of the two groups were similar. A total of 62 participants (placebo, 30; vitamin D, 32) completed the study protocol. At the end of the study period, the 25-hydroxyvitamin D [25(OH)D] levels were significantly higher in the vitamin D group than in the placebo group (35.4 ± 8.5 ng/mL vs. 18.4 ± 7.3 ng/mL, p < 0.001). There was no difference in HOMA-IR or changes in arterial stiffness (placebo, 21, vitamin D, 24) between the groups.
Our data suggest that high-dose vitamin D supplementation might be effective in terms of elevating 25(OH)D levels. However, we identified no beneficial effects on cardiovascular risk in type 2 diabetes, including IR and arterial stiffness.
Available from: Frank H Mose
- "Renin expression is highly elevated in VDR null mice, which leads to systemic hypertension, cardiac hypertrophy and heart failure . Although an inverse relationship between 1,25(OH)2D and PRC has been documented in humans , prospective clinical trials have not confirmed this relationship satisfactorily. The results of a descriptive study of 17 children and young adults with hereditary vitamin D resistant rickets were remarkable, as none of the patients had hypertension, left ventricular hypertrophy or PRA elevation . "
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ABSTRACT: Vitamin D receptor activators reduce albuminuria, and may improve survival in chronic kidney disease (CKD). Animal studies suggest that these pleiotropic effects of vitamin D may be mediated by suppression of renin. However, randomized trials in humans have yet to establish this relationship.
In a randomized, placebo-controlled, double-blinded crossover study, the effect of oral paricalcitol (2 mug/day) was investigated in 26 patients with non-diabetic, albuminuric stage III-IV CKD. After treatment, plasma concentrations of renin (PRC), angiotensin II (AngII) and aldosterone (Aldo) were measured. GFR was determined by 51Cr-EDTA clearance. Assessment of renal NO dependency was performed by infusion of NG-monomethyl-L-arginine (L-NMMA). Albumin excretion rate (AER) was analyzed in 24-h urine and during 51Cr-EDTA clearance.
Paricalcitol did not alter plasma levels of renin, AngII, Aldo, or urinary excretion of sodium and potassium. A modest reduction of borderline significance was observed in AER, and paricalcitol abrogated the albuminuric response to L-NMMA.
In this randomized, placebo-controlled trial paricalcitol only marginally decreased AER and did not alter circulating levels of renin, AngII or Aldo. The abrogation of the rise in albumin excretion by paricalcitol during NOS blockade may indicate that favourable modulation of renal NO dependency could be involved in mediating reno-protection and survival benefits in CKD.Trial registration: ClinicalTrials.gov identifier: NCT01136564.
Available from: link.springer.com
- "Lower 25OHD levels and higher BMI values have been associated with higher plasma renin and aldosterone concentrations in Indian subjects with hypertension . Vitamin D metabolites have been inversely associated with circulating renin . Genetic disruption of the VDR results in overstimulation of the RAS with increasing renin and angiotensin II productions, leading to high blood pressure and cardiac hypertrophy. "
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ABSTRACT: The prevalence rates of overweight and obesity are considered an important public issue in the United States, and both of these conditions are increasing among both children and adults. There is evidence of aberrations in the vitamin D-endocrine system in obese subjects. Vitamin D deficiency is highly prevalent in patients with obesity, and many studies have demonstrated the significant effect of calcitriol on adipocytes. Genetic studies have provided an opportunity to determine which proteins link vitamin D to obesity pathology, including the vitamin D receptor, toll-like receptors, the renin-angiotensin system, apolipoprotein E, vascular endothelial growth factor, and poly (ADP-ribose) polymerase-1. Vitamin D also exerts its effect on obesity through cell-signaling mechanisms, including matrix metalloproteinases, mitogen-activated protein kinase pathways, the reduced form of nicotinamide adenine dinucleotide phosphate, prostaglandins, reactive oxygen species, and nitric oxide synthase.
In conclusion, vitamin D may have a role in obesity. The best form of vitamin D for use in the obese individuals is calcitriol because it is the active form of the vitamin D3 metabolite, its receptors are present in adipocytes, and modulates inflammatory cytokine expression.
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