Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
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PMID:1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. 2436 72

Vitamin D is one of the oldest hormones that have been made in the earliest life forms for over 750 million years. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. Vitamin D is metabolized in the liver and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. 1,25(OH)(2)D receptors (VDR) are present not only in the intestine and bone, but in a wide variety of other tissues, including the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, gonads, etc. 1,25(OH)(2)D is one of the most potent substances to inhibit proliferation of both normal and hyperproliferative cells and induce them to mature. It is also recognized that a wide variety of tissues, including colon, prostate, breast, and skin have the enzymatic machinery to produce 1,25(OH)(2)D. 1,25(OH)(2)D and its analogs have been developed for treating the hyperproliferative disease psoriasis. Vitamin D deficiency is a major unrecognized health problem. Not only does it cause rickets in children, osteomalacia and osteoporosis in adults, but may have long lasting effects. Chronic vitamin D deficiency may have serious adverse consequences, including increased risk of hypertension, multiple sclerosis, cancers of the colon, prostate, breast, and ovary, and type 1 diabetes. There needs to be a better appreciation of the importance of vitamin D for overall health and well being.
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PMID:Vitamin D: A millenium perspective. 1252 May 30

It is remarkable that phytoplankton and zooplankton have been producing vitamin D for more than 500 million years. The role of vitamin D in lower non-vertebrate life forms is not well understood. However, it is critically important that most vertebrates obtain an adequate source of vitamin D, either from exposure to sunlight or from their diet, in order to develop and maintain a healthy mineralized skeleton. Vitamin D deficiency is an unrecognized epidemic in most adults who are not exposed to adequate sunlight. This can precipitate and exacerbate osteoporosis and cause the painful bone disease osteomalacia. Once vitamin D is absorbed from the diet or made in the skin by the action of sunlight, it is metabolized in the liver to 25-hydroxyvitamin D [25(OH)D] and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D interacts with its nuclear receptor (VDR) in the intestine and bone in order to maintain calcium homeostasis. The VDR is also present in a wide variety of other tissues. 1,25(OH)2D interacts with these receptors to have a multitude of important physiological effects. In addition, it is now recognized that many tissues, including colon, breast and prostate, have the enzymatic machinery to produce 1,25(OH)2D. The insights into the new biological functions of 1,25(OH)2D in regulating cell growth, modulating the immune system and modulating the renin-angiotensin system provides an explanation for why diminished sun exposure at higher latitudes is associated with increased risk of dying of many common cancers, developing type 1 diabetes and multiple sclerosis, and having a higher incidence of hypertension. Another calciotropic hormone that is also produced in the skin, parathyroid hormone-related peptide, is also a potent inhibitor of squamous cell proliferation. The use of agonists and antagonists for PTHrP has important clinical applications for the prevention and treatment of skin diseases and disorders of hair growth.
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PMID:Evolution and function of vitamin D. 1289 11

Our previous studies showed vitamin D deficiency results in increased cardiac contractility, hypertrophy and fibrosis and has profound effects on heart proteomics, structure and function in rat. In this study we found that the heart in vitamin D receptor knockout (VDR-KO) mice is hypertrophied. Six homozygous VDR knockout (-/-), six wild type (+/+) and six heterozygous (+/-) mice were fed a diet containing 2% Ca, 1.25% P and 20% lactose to maintain normal blood calcium and phosphate levels for 12 months. Tail-cuff blood pressure was performed on all mice. Blood pressure determinations showed no differences in systolic or mean blood pressure in WT (+/+), KO (-/-) or HETERO (+/-) mice at 3 and 6 months. However, decreased systolic BP in the KO mice relative to WT at 9 months of age was observed. ECG analysis showed no significant differences in the intact KO, HETERO or WT mice. The mice were killed at 12 months. Heart weight/body weight ratio was 41% (P<.003) greater in the KO mice versus WT and HETERO was 19% (P<.05) increased versus WT. Other VDR-KO tissues did not display hypertrophy. Cross sectional and longitudinal analysis of the heart myofibrils showed highly significant cellular hypertrophy in VDR-KO mice. Trichrome staining of heart tissue showed marked increase in fibrotic lesions in the KO mice. Analysis of plasma renin activity, angiotensin II (AII) and aldosterone levels showed elevated but not significantly different renin activity in KO versus WT and no significant differences in AII or aldosterone levels. Our data do not support the concept that the renin-angiotensin system or hypertension are the factors that elicit these changes. Data presented here reveal that ablation of the VDR signaling system results in profound changes in heart structure. We propose that calcitriol acts directly on the heart as a tranquilizer by blunting cardiomyocyte hypertrophy.
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PMID:Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse. 1727 89

The basic function of vitamin D3 in human body is to maintain the calcium-phosphate homeostasis. Its metabolic function is mediated by the nuclear VDR receptor. The existance of vitamin D3 receptors outside tissues and organs which take part in calcium-phosphate metabolism has resulted in not treating it as an anti rickets agent only. Lower arterial blood pressure observed in people living in sunny areas and decrease of arterial blood pressure values after exposure to UVB radiation could confirm the relationship between vitamin D3 and hypertension. Perhaps through its influence on calcium-phosphate metabolism, RAA system, immune system, control of endocrine glands and endothelium function the vitamin D3 contributes to lowering arterial blood pressure and lessening the risk of cardiovascular disease.
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PMID:[Role of vitamin D3 in arterial blood pressure control]. 1829 57

Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin-megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.
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PMID:Vitamin D and aging. 1944 37

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.
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PMID:Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors. 2009 93

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Traditional causes such as diabetes, smoking, aging and hypertension do not fully explain the high rate of morbidity from cardiovascular disease seen in these patients. The renin-angiotensin-aldosterone system (RAAS) regulates extracellular volume homeostasis, which contributes to blood pressure stability. Overactivity of this system is involved in the pathophysiology of cardio-renal disease. New evidence suggests that vitamin D receptor activators (VDRAs) have a suppressive effect on the RAAS; however, VDRAs also have anti-inflammatory and anti-fibrotic effects. We have demonstrated that paricalcitol, a VDRA, ameliorates left ventricular hypertrophy (LVH) in uremic rats by up-regulating the VDR, decreasing myocardial PCNA and also decreasing myocardial oxidative stress. Thus, paricalcitol can suppress the progression of LVH, myocardial and perivascular fibrosis and myocardial arterial vessel thickness presumably by up-regulating the VDR. Paricalcitol may prove to have a substantial beneficial effect on cardiac disease and its outcome in patients with CKD. Prospective randomized studies in CKD patients are necessary to confirm these results.
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PMID:Myocardial effects of VDR activators in renal failure. 2023 14

Vitamin D has an essential role in calcium metabolism and bone health. Vitamin D3 or cholecalciferol is synthesized from 7-dehydrocholesterol or provitamin D3, by sunlight ultraviolet radiation to the skin. 7-dehydrocholesterol is subsequently hydroxylated in the liver and then in the kidney to produce 1,25-(OH)2D3, the active metabolite that binds to specific receptors (VDR) in target tissues, mainly bone and intestine. Other tissues, such as the immune and cardiovascular system, have also VDR. Vitamin D deficiency can induce rickets in children and osteomalacia and osteoporosis in adults. A possible inverse association between vitamin D levels and the prevalence of metabolic syndrome has been proposed. Vitamin D deficiency increases the risk of type 1 diabetes, insulin resistance, and hypertension, key components of this syndrome. However, other studies have not confirmed this association. Further clinical and experimental studies are needed to ascertain the role of vitamin D in metabolic syndrome.
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PMID:[Association between vitamin D deficiency and metabolic syndrome]. 2127 81

Vitamin D deficiency has been linked to hypertension and an increased prevalence of cardiovascular risk factors and disease. Studies in vitamin D receptor knockout (VDR KO) mice revealed an overstimulated renin-angiotensin system (RAS) and consequent high blood pressure and cardiac hypertrophy. VDR KO mice correspond phenotypically and metabolically to humans with hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR). There are no data on the cardiovascular system in human HVDRR. To better understand the effects of vitamin D on the human cardiovascular system, the RAS, blood pressure levels, and cardiac structures were examined in HVDRR patients. Seventeen patients (9 males, 8 females, aged 6 to 36 years) with hereditary HVDRR were enrolled. The control group included age- and gender-matched healthy subjects. Serum calcium, phosphorous, creatinine, 25-hydroxyvitamin D [25(OH)D],1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ], parathyroid hormone (PTH), plasma rennin activity (PRA), aldosterone, angiotensin II (AT-II), and angiotensin-converting enzyme (ACE) levels were determined. Ambulatory 24-hour blood pressure measurements and echocardiographic examinations were performed. Serum calcium, phosphorus, and alkaline phosphatase values were normal. Serum 1,25(OH)(2) D(3) and PTH but not PRA and ACE levels were elevated in the HVDRR patients. AT-II levels were higher than normal in the HVDRR patients but not significantly different from those of the controls. Aldosterone levels were normal in all HVDRR patients. No HVDRR patient had hypertension or echocardiographic pathology. These findings reveal that 6- to 36-year-old humans with HVDRR have normal renin and ACE activity, mild but nonsignificant elevation of AT-II, normal aldosterone levels, and no hypertension or gross heart abnormalities.
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PMID:The renin-angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D-resistance rickets (HVDRR). 2159 Jul 41


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