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)

Epidemiological studies reporting an inverse association between sunlight exposure and risk for cancers of the breast, colon, and prostate, have not yet been explained. Since ultraviolet (UV) light promotes dermal vitamin D generation, studies suggesting that dietary calcium and vitamin D may likewise have cancer-preventive activity are potentially of relevance. UV light, calcium, and vitamin D have the common property of suppressing parathyroid hormone (PTH) production; these considerations raise the possibility that PTH may have promotional activity for certain cancers. PTH might function indirectly in this regard, by increasing hepatic production of the progression growth factor IGF-I, a likely cancer promoter. A more direct role is suggested by recent evidence that many cancers express receptors for PTH/PTH-related protein; these receptors mediate co-mitogenic and/or pro-invasive signals in some cancers. High risk for previous or concurrent neoplasms has been reported in patients with parathyroid adenomas. In light of the increase in cancer risk associated with hypertension, it is notable that PTH levels are typically increased in salt-sensitive hypertensives. Prospective case-control studies examining serum PTH in relation to subsequent cancer risk appear warranted.
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PMID:Parathyroid hormone may be a cancer promoter - an explanation for the decrease in cancer risk associated with ultraviolet light, calcium, and vitamin D. 1078 92

Evidence implicates pivotal roles for parathyroid hormone-related protein (PTHrP) in stimulating cell growth and differentiation, placental calcium transport, and placental vasodilatation. As spontaneously hypertensive rat (SHR) fetuses are growth restricted compared with those of its normotensive control, the Wistar Kyoto (WKY) rat, we examined intrauterine PTHrP and total and ionic calcium concentrations in these rats. Fetal plasma PTHrP concentrations, but not total calcium concentrations, were lower in the SHR compared with WKY (P < 0.05). SHR placental concentrations of PTHrP were lower than in WKY (P < 0.03) and failed to show the increase observed in WKY near term (P < 0.05). PTHrP concentrations in amniotic fluid from SHR were not raised near term and were lower compared with WKY (P < 0.0005). The increased ionic calcium concentrations in amniotic fluid in the WKY near term (P < 0.05) were not detected in the SHR. Thus SHR fetal plasma, placental, and amniotic fluid PTHrP concentrations were reduced and associated with fetal growth restriction. We suggest that PTHrP may play a role in the etiology of both growth restriction during pregnancy and hypertension later in life.
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PMID:Reduced fetal, placental, and amniotic fluid PTHrP in the growth-restricted spontaneously hypertensive rat. 1089 61

Calbindin-D28k is an intracellular protein with high affinity for calcium. In the kidney, this protein is exclusively localized in the distal tubule and in the proximal part of the collecting ducts. Functionally, calbindin-D28k is supposed to be involved in the regulation of the reabsorption of calcium and possibly magnesium in the distal nephron though the exact regulatory mechanisms are not yet known. Thus, several theories regarding the functional role of calbindin-D28k have been proposed: The carrier theory describes calbindin-D28k as a transport protein which binds calcium and then transports it from the luminal to the basolateralcell membrane. The buffer theory assumes that calbindin-D28k functions by binding calcium ions to prevent intracellular calcium concentrations from reaching toxic levels. The activator theory describes that calbindin-D28k increases the activity of calcium channels or the enzymatic activity of the Ca++-Mg++-ATPase in the luminal membrane and thereby increases the tubular reabsorption of calcium. The renal calbindin-D28k is dependent upon vitamin D. Pharmacological doses of the active vitamin D metabolite 1,25-(OH)2D increases the concentrations of renal calbindin-D28k, whereas the concentration of calbindin-D28k is low in conditions with reduced levels of circulating 1,25-(OH)2D. Likewise, plasma calcium concentrations, uremia and hypertension affect calbindin-D28k expression. However, several studies have rendered probable the effect of additional factors in the regulation of renal calbindin-D28k. The aim of the present dissertation therefore was to examine the regulation of renal calbindin-D28k in a series of physiological and pathophysiological conditions established in vivo in the rat. A possible correlation between hypertension and calbindin-D28k was examined in three models of experimental hypertension: the genetically defined spontaneous hypertensive rat, the salt-sensitive Dahl rat and the renovascular hypertensive rat. These three models clearly demonstrated three separate patterns in the calcium metabolism, but the studies were unable to support a role for calbindin-D28k in the development of hypertension. In all three models the development of hypertension caused an increased plasma 1,25-(OH)2D. This increase was accompanied by either unaltered or reduced levels of renal calbindin-D28k possibly secondary to a cellular resistance against 1,25-(OH)2D. Magnesium binds to calbindin-D28k with a relatively high affinity. The regulation of urinary magnesium excretion takes place in the distal tubule where calbindin-D28k is found in high concentrations. Therefore, a possible relation between magnesium and calbindin-D28k was examined. The studies demonstrated not previously known connections between magnesium intake, urinary magnesium excretion and renal calbindin-D28k which suggests that this protein is involved in the regulation of magnesium homeostasis by the kidney. Calcitonin increases the reabsorption of calcium in the distal tubule. Therefore, the effect ofcalcitonin on renal calbindin-D28k was examined both by eliminating the endogeneous calcitonin production by a selective thyroidectomy followed by an autotransplantation of the parathyroid glands and further by infusion of calcitonin. These studies demonstrated unchanged concentrations of renal calbindin-D28k. It was concluded that the increased calcium reabsorption induced by calcitonin in the distal tubule is not mediated by calbindin-D28k. Urinary calcium excretion is in part regulated by the action of PTH on calcium reabsorption in the distal nephron. Previous reports of increased expression of renal calbindin-D28k in uremic rats led us to suggest that secondary hyperparathyroidism associated with uremia induced the synthesis of renal calbindin-D28k. Therefore, the effect of PTH was examined in a study comprising selective parathyroidectomy and infusions of PTH, PTHrP, 1,25-(OH)2D and calcium. (ABSTRACT TRUNCATED)
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PMID:Regulation of renal calbindin-D28K. 1109 7

Intrauterine parathyroid hormone-related protein (PTHrP) concentrations are reduced in association with growth restriction in the spontaneously hypertensive rat (SHR) compared to those of its normotensive control, the Wistar Kyoto (WKY) rat, implicating PTHrP as a pivotal fetal growth factor. The aim of this study was to examine, by embryo cross-transplanation between SHR and WKY, whether the mother, fetus, or both, are responsible for the suppressed SHR amniotic fluid PTHrP. One-day-old SHR embryos were gestated in either an SHR (SHR-in-SHR) or WKY (SHR-in-WKY) surrogate, similarly one-day-old WKY embryos were gestated in either an SHR (WKY-in-SHR) or WKY (WKY-in-WKY) mother. At 20 days gestation, maternal plasma and amniotic fluid samples were collected and assayed for PTHrP concentrations. Data were analysed by two-way ANOVA (mean+/-sem, n=5-9 mothers/group). There were no differences in litter number or maternal plasma PTHrP concentrations. Fetal weight (P< 0.009), fetal/placental weight ratio (P< 0.004) and amniotic fluid PTHrP concentrations (P< 0.001) were lower and amniotic fluid volume (P< 0.0001) was higher with an SHR fetus compared to the WKY fetus irrespective of maternal strain. Thus, the SHR fetus is growth restricted and has suppressed amniotic fluid PTHrP, which are largely determined by the fetus or gestational tissues and are independent of maternal hypertension or maternal PTHrP. We suggest that the low SHR amniotic fluid PTHrP may play a role in the development of SHR growth restriction.
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PMID:The spontaneously hypertensive rat fetus, not the mother, is responsible for the reduced amniotic fluid PTHrP concentrations and growth restriction. 1150 33

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

Preeclampsia is a disorder associated with pregnancy that affects both the mother and the fetus. Typical features of the disease are maternal hypertension, proteinuria, and edema as well as fetal growth retardation. Although the etiological details are still being debated, a consensus exists that the starting point is deficient placentation in the first half of pregnancy. The crucial early steps are reduced trophoblast invasiveness and enhanced apoptotic death. In the present review, we demonstrate that parathyroid hormone-related protein is involved not only in the maternal and fetal failures but also in the etiological aspects of the disease. We hypothesize that reduced local production of the peptide is a major causative event.
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PMID:Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures. 1528 39

In vivo, vascular smooth muscle cells (VSMC) are continuously exposed to mechanical cyclic stretch as a result of the pulsatile blood flow from the cardiac contractile cycle. Stretch is altered in pathologic conditions and contributes to vascular remodeling by modulating VSMC proliferation and death. Parathyroid hormone-related protein (PTHrP) is a locally produced poly-protein that regulates cell growth. It was shown previously that PTHrP inhibits VSMC proliferation through the auto/paracrine pathway by interacting with its receptor, the PTH1R, but stimulates VSMC proliferation through the intracrine pathway by translocating into the nucleus. In the current study, VSMC that were isolated from both resistance and compliance vessels were used to study the role of PTHrP in VSMC proliferation under experimental stretch. It is shown that PTHrP gene expression is upregulated by stretch and that PTHrP opposes the inhibitory effect induced by stretch on VSMC proliferation through the intracrine pathway. In addition, it is demonstrated that PTHrP expression is controlled at the post-transcriptional level by stretch. Taken together, these results strongly suggest that PTHrP plays a critical role in the modulation of VSMC proliferation in response to stretch. Thus, in conditions in which stretch is increased, such as in hypertension or in restenosis after angioplasty, PTHrP may contribute to vessel hyperplasia.
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PMID:Role of parathyroid hormone-related protein in the regulation of stretch-induced renal vascular smooth muscle cell proliferation. 1557 4

We have recently demonstrated that arterial PTHrP expression and cardiovascular responses to this protein are altered in SHR compared with normotensive animals, Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats. To investigate whether the slightly, but significantly decreased, aortic PTHrP gene expression observed in SHR, compared to that of normotensive animals, may play a causative role in the maintenance of the elevated arterial blood pressure (ABP) of the SHR, we transfected a hepatic lobe with a PTHrP expression vector in a sense and antisense orientation. At 24 and 48 hours, sense pSV2neo-ECE induced a significant five-fold increase in PTHrP mRNA abundance with respect to antisense pSV2neo-ECE and vehicle. This increment in the PTHrP mRNA induced by the sense PTHrP expression vector was totally inhibited by the co-administration of the antisense PTHrP expression vector. At the same time, we observed a significant decrease of mean ABP (MABP) in SHR transfected with the sense pSV2neo-ECE to similar values as those obtained in the normotensive strain. Neither antisense PTHrP expression vector nor vehicle had any significant effect in any strain. Again, the effect of the sense PTHrP expression vector on MABP was blocked by the simultaneous treatment with the antisense PTHrP expression vector. At 48 hours, the hypotensive effect of the sense pSV2neo-ECE in SHR was reverted by the i.v. bolus injection of a specific competitive PTHrP receptor antagonist such as Nle8,18,Tyr34-bPTH(3-34)amide. We propose that a defect of this potent local vasodilator may contribute to the development and/or maintenance of arterial hypertension in SHR. This defect can be ameliorated by transfecting tissues with protein-exporting capabilities, such as the liver. Finally, our work adds additional data to a cumulative body of evidence suggesting that it might be possible to design an effective gene therapy to treat the common polygenic and multifactorial form of hypertension by increasing the activity of potent and physiological vasodilators.
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PMID:Parathyroid hormone-related protein overexpression decreases blood pressure in spontaneously hypertensive rats. 1592 Oct 71

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D3 and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as alpha-actin and SM-22alpha, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. Furthermore, putative calcification inhibitory molecules have been identified using mouse mutational analyses, including MGP, beta-glucosidase, fetuin-A, and osteoprotegerin. Mutant mice deficient in these molecules present with enhanced cardiovascular calcification, demonstrating that specific molecules are normally important in suppressing vascular calcification. These findings suggest that the balance of inducers, such as phosphate, and inhibitors, such as MGP, fetuin-A, and others, are likely to control whether or not calcification occurs under pathological conditions.
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PMID:Vascular calcification in chronic kidney disease. 1650 29

We previously reported that PTHrP-induced renal vasodilation is impaired in mature spontaneously hypertensive rats (SHR) through down-regulation of the type 1 PTH/PTHrP receptor (PTH1R), a feature that contributes to the high renal vascular resistance in SHR. Here we asked whether this defect represents a prime determinant in genetic hypertension or whether it is secondary to angiotensin II (Ang II) and/or the mechanical forces exerted on the vascular wall. We found that the treatment of SHR with established hypertension by the Ang II type 1 receptor antagonist, losartan, reversed the down-regulation of PTH1R expression in intrarenal small arteries and restored PTHrP-induced vasodilation in ex vivo perfused kidneys. In contrast, the PTH1R deregulation was not found in intrarenal arteries isolated from prehypertensive SHR. Moreover, this defect, which is not seen in extrarenal vessels (aorta, mesenteric arteries) from mature SHR appeared kidney specific in accordance with the acknowledged enrichment of interstitial Ang II in this organ and its enhancement in SHR. In deoxycorticosterone-acetate-salt rats, an Ang II-independent model of hypertension, renovascular PTH1R expression and related vasodilation were not altered. In SHR-derived renovascular smooth muscle cells (RvSMCs), the PTH1R was spontaneously down-regulated and its transcript destabilized, compared with Wistar RvSMCs, both effects being antagonized by losartan. Exogenous Ang II elicited down-regulation of PTH1R mRNA in RvSMCs from Wistar rats. Together, these data demonstrate that Ang II acts via the Ang II type 1 receptor to destabilize PTH1R mRNA in the renal vessel in the SHR model of genetic hypertension. This process is kidney specific and independent from blood pressure increase.
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PMID:Abnormal renovascular parathyroid hormone-1 receptor in hypertension: Primary defect or secondary to angiotensin ii type 1 receptor activation? 1672 97


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