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Vitamin D and the Renin-Angiotensin System
Abstract
The renin-angiotensin system (RAS) is a central regulator of renal and cardiovascular functions. Over-activation of the RAS leads to renal and cardiovascular disorders, such as hypertension and chronic kidney disease, the major risk factors for stroke, myocardial infarction, congestive heart failure, progressive atherosclerosis, and renal failure. Mounting epidemiological and clinical evidence has demonstrated an association of vitamin D deficiency or insufficiency with increased risks of renal and cardiovascular diseases. Long-term vitamin D deficiency can lead to over-activation of the RAS. Because of the broad involvement of the RAS in the development of renal and cardiovascular diseases, such findings have invaluable pathophysiological and therapeutic implications. They provide a mechanistic insight into the ever-increasing epidemiological and clinical evidence linking vitamin D deficiency to renal and cardiovascular problems in the general population. They also provide a molecular basis to explore the therapeutic potentials of vitamin D and its analogs in the prevention and intervention of these diseases. Therefore, the rising prevalence of hypertension and chronic kidney disease around the world attests the urgent need for new and more effective therapeutic methods.
... Additionally, vitamin D receptor knockout mouse exhibit blighted kidney functions despite having normal plasma sodium and potassium homeostasis [81]. These knockout mice also exhibit high blood pressure, cardiac phy, and aberrant drinking behavior, and these aberrations can be ameliorated by treatment with RAS blockers (i.e. an ACE inhibitor or Ang II receptor antagonist) [90] . Mice lacking functional 1- -hydroxylase, the enzyme that produces active vitamin D, also consistently showed elevated kidney renin expression that can be reversed by administration of 1,25(OH) 2 D 3 [90] . ...
... These knockout mice also exhibit high blood pressure, cardiac phy, and aberrant drinking behavior, and these aberrations can be ameliorated by treatment with RAS blockers (i.e. an ACE inhibitor or Ang II receptor antagonist) [90] . Mice lacking functional 1- -hydroxylase, the enzyme that produces active vitamin D, also consistently showed elevated kidney renin expression that can be reversed by administration of 1,25(OH) 2 D 3 [90] . The excess generation of renin that accompanies abnormal vitamin D metabolism is believed to be independent of calcium metabolism [149] ; the ability of vitamin D replenishment to reverse excess renin production has been attributed to vitamin D having a negative regulatory influence at the renin gene promoter [91]. ...
The traditional renin-angiotensin system (RAS) components have been studied extensively since the rate-limiting component of RAS, renin, was first characterized. The ongoing identification of various novel RAS components and signaling pathways continues to elaborate the complexity of this system. Regulation of RAS according to the conventional and contemporary views of its functions in various tissues under pathophysiological conditions is a main treatment strategy for many metabolic diseases. The local pancreatic RAS, first proposed to exist in pancreatic islets two decades ago, could regulate islet function and glycemic control via influences on islet cell mass, inflammation, and ion channels. Insulin secretion, the major function of pancreatic islets, is controlled by numerous factors. Among these factors and of particular interest are glucagon-like peptide-1 (GLP-1) and vitamin D, which may regulate islet function by directly binding receptors on islet beta cells. These factors may work with local RAS signaling in islets to protect and maintain islet function under diabetic and hyperglycemic conditions. In this concise review, the local islet RAS will be discussed with particular attention being paid to recent notable findings.
... Calcitriol (25-OH vitamin D3), the active form of vitamin D that is usually made in the kidney, exerts protective effects on lung injury through modulating components of the renin-angiotensin system (RAS) such as ACE1 and ACE2, renin and angiotensin II [252]. 1, 25-dihydroxy vitamin D suppresses renin gene expression, thereby inhibiting the renin-angiotensin system and reducing the activity of the angiotensinconverting enzyme [256,257]. Vitamin-D deficiency may also pose an increased susceptibility to enveloped virus infections such as HIV, Hepatitis, Dengue, and Respiratory Syncytial virus infection [258]. The following studies report an indirect role of vitamin D on coronaviral infections. ...
... Calcitriol (25-OH vitamin D3), the active form of vitamin D that is usually made in the kidney, exerts protective effects on lung injury through modulating components of the renin-angiotensin system (RAS) such as ACE1 and ACE2, renin and angiotensin II 252 . 1,25-dihydroxy vitamin D suppresses renin gene expression, thereby inhibiting the renin-angiotensin system and reducing the activity of the angiotensin-converting enzyme256,257 . Vitamin-D deficiency may also pose an increased susceptibility to enveloped virus infections such as HIV, Hepatitis, Dengue, and Respiratory Syncytial virus infection258 .The following studies report an indirect role of vitamin D on coronaviral infections. ...
Within the micro and nano world, tiny membrane-enclosed bits of material are more or less free to move and act as communication tools within cells, between cells, between different tissues and between organisms in global environment. Based on the mechanism of membrane budding and vesiculation that includes all types of cells, in this review, we attempted to present a review on SARS-CoV-2 virus actions in compartments of different scales (cells and their surroundings, tissues, organisms and society). Interactions of the virus with cells on a molecular level, with neural system, endothelium, hematopoietic system, gastrointestinal system and genitourinary system. Transmission route between organisms and between mother and fetus are considered. Also, transmission of virus through contact with materials and with environment, the suggested measures to prevent contamination with the virus and to support the organism against the disease are given.
... Vitamin D and hypertension. The effect of vitamin D on blood pressure was suggested to be related to its suppressive actions on the renin-angiotensin-aldosterone system, 91 inhibition of hyperparathyroidism, direct actions on the vessel wall and protection from oxidative stress. 92 Vdr-deficient mice have increased blood pressure, which is mediated by renin and plasma angiotensin II elevation. ...
Study design:
Narrative review.
Objectives:
This review provides an overview of the etiological factors and consequences of vitamin D insufficiency in relation to spinal cord injury (SCI) as well as important considerations for vitamin D supplementation.
Setting:
Montreal, Canada.
Methods:
Literature search.
Results:
Vitamin D insufficiency is common in SCI individuals owing to the presence of many contributing factors including limited sun exposure and intake, use of medication and endocrine perturbations. Although there are several biological plausible mechanisms by which vitamin D may act upon musculoskeletal and cardiometabolic health, the impact of vitamin D insufficiency on such systems remains ill defined in SCI. In the absence of guidelines for the management of vitamin D insufficiency in this high-risk population and in an attempt to provide clinical guidance, considerations for vitamin D supplementation such as the type of vitamin D, dosing regimens and toxicity are discussed and tentative recommendations suggested with particular reference to issues faced by SCI patients.
Conclusion:
Although high rates of vitamin D insufficiency are encountered in SCI individuals, its consequences and the amount of vitamin D required to prevent insufficiency are still unknown, indicating a need for more intervention studies with well-defined outcome measures. Routine screening and monitoring of vitamin D as well as treatment of suboptimal status should be instituted in both acute and chronic setting. The close interactions between vitamin D and related bone minerals should be kept in mind when supplementing SCI individuals, and practices should be individualized with clinical conditions.Spinal Cord advance online publication, 20 September 2016; doi:10.1038/sc.2016.131.
... Exposure to ultraviolet B irradiation reduced arterial pressure in a cohort of patients with mild hypertension [17], and Pfeifer et al reported that vitamin D supplementation reduced systolic blood pressure in elderly women with low vitamin D status [18]. The linkage between vitamin D and blood pressure may relate, in part, to the fact that the vitamin is a negative regulator of renin release [19]. Indeed, vitamin D receptornull mice exhibit increased renal renin mRNA expression, elevated plasma levels of angiotensin II, hypertension and cardiac hypertrophy [20]. ...
Vitamin D deficiency is common in Arab countries particularly among women. This is the result of a low dietary intake of the vitamin, limited exposure to sunlight (a paradox in view of the high sunshine figures), skin colour, obesity and high parity. Apart from its adverse effects on bone in women and their offspring, vitamin D deficiency has the potential to cause or exacerbate heart failure through a number of mechanisms including activation of the renin-angiotensin system and increased arterial pressure. Accordingly, we propose that ensuring adequate vitamin D levels in Arab women will have a much greater impact on health than just the prevention of bone disease. In particular, we suggest that prevention and correction of vitamin D deficiency will reduce the incidence of heart failure and, for Arab women with established heart failure and vitamin D deficiency, improve cardiac function.
Die Erfolgsgeschichte des Vitamin D ist in den vergangenen 75 Jahren geschrieben worden. Sie begann mit der Erkenntnis, dass dieses Vitamin als antirachitischer Faktor fungiert und reicht bis in unsere Zeit hinein, in der es als Hormon mit Effekten im gesamten Körper eingestuft wurde. In der Evolution existiert diese Substanz aber schon über 750 Millionen Jahre und wird von Phytoplankton unter Sonnenbestrahlung synthetisiert.
Vitamin D (D3) status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, few placebo-controlled intervention data are available. We aimed to assess the effect of large doses of parenteral D3 on glycosylated haemoglobin (HbA1c) and estimates of insulin action (homeostasis model assessment insulin resistance: HOMA-IR) in patients with stable T2DM.
We performed a prospective, randomised, double-blind, placebo-controlled pilot study at a single university care setting in Switzerland. Fifty-five patients of both genders with T2DM of more than 10 years were enrolled and randomised to either 300,000 IU D3 or placebo, intramuscularly. The primary endpoint was the intergroup difference in HbA1c levels. Secondary endpoints were: changes in insulin sensitivity, albuminuria, calcium/phosphate metabolism, activity of the renin-aldosterone axis and changes in 24-hour ambulatory blood pressure values.
After 6 months of D3 supply, there was a significant intergroup difference in the change in HbA1c levels (relative change [mean ± standard deviation] +2.9% ± 1.5% in the D3 group vs +6.9% ± 2.1% the in placebo group, p = 0.041) as HOMA-IR decreased by 12.8% ± 5.6% in the D3 group and increased by 10% ± 5.4% in the placebo group (intergroup difference, p = 0.032). Twenty-four-hour urinary albumin excretion decreased in the D3 group from 200 ± 41 to 126 ± 39, p = 0.021). There was no significant intergroup difference for the other secondary endpoints.
D3 improved insulin sensitivity (based on HOMA-IR) and affected the course of HbA1c positively compared with placebo in patients with T2DM.
Pancreatic islets secrete multiple factors that act as endocrine, paracrine, and/or autocrine pathways in regulating pancreatic endocrine function. As such, the islets perform critical biological activities in synthesizing metabolic peptide hormones, notably insulin and regulating body glucose homeostasis. These functions are controlled by various conditions and signaling molecules, particularly nutrients like glucose levels. However, more and more clinically relevant regulators, including molecules which stimulate islet beta-cell metabolism, regulate beta-cell [Ca(2+)] homeostasis and related channels or adjust beta-cell membrane, and nuclear receptors activity continue to be discovered and characterized. Of great interest in this context, glucagon-like peptide-1 can improve glycemic control by regulating insulin secretion and islet cell mass; vitamin D can regulate islet physiology directly by binding its receptors; in addition, the peptide hormone angiotensin II has been implicated in islet function and exhibits effects on islet cell secretion as well as cell mass. In this chapter, these three novel regulators in islet function and thus its clinical relevance to type 2 diabetes mellitus will undergo critical appraisal. Since all of these molecules have biological interactions with pancreatic islets, potential relationships may exist among them and they will also be discussed.
Eine Monotherapie mit Vitamin D und Calcium ist zur Behandlung der postmenopausalen Osteoporose nicht geeignet. Die Supplementation von Calcium und Vitamin D(3) ist aber generell als Basistherapie bei Patienten mit Risikofaktoren und obligat als additive Begleittherapie bei jeder medikamentösen Osteoporosetherapie indiziert und sogar unerlässlich (siehe DVO-Leitlinien). Nach mehrjähriger Behandlung mit effektiven Antiosteoporotika wird oft Calcium plus Vitamin D allein im Sinne einer "Erhaltungstherapie" fortgeführt. Die Datenlage zur fraktursenkenden Wirkung von Calcium und/oder Vitamin D erlaubt folgende Einschätzungen: Wirkung gesichert: Verminderung von Schenkelhalsfrakturen bei Frauen in Altenheimen mit einem Calcium- und Vitamin-D-Mangel durch die kombinierte Gabe von Vitamin D plus Calcium. Wirkung wahrscheinlich: Verminderung von peripheren Frakturen bei Frauen und Männern im höheren Lebensalter mit Calcium- und Vitamin-D-Mangel durch die kombinierte Gabe von Vitamin D plus Calcium. Wirkung möglich: Verminderung von peripheren Frakturen und Wirbelkörperfrakturen bei Männern und Frauen in allen Altersklassen durch eine Optimierung der Calcium- und Vitamin-D-Versorgung.Bei älteren Menschen muss die Vitamin-D-Gabe wegen der mangelhaften Produktion in der Haut Sommer wie Winter erfolgen. Die Serumkonzentration an 25-Hydroxyvitamin D sollte mindestens 20 ng/mL und durchschnittlich 30 ng/mL betragen. Um diesen Spiegel zu erreichen, ist eine tägliche Aufnahme von ca. 800 IE (20 mug) Vitamin D erforderlich. Eine Vitamin-D- und Calcium-Zufuhr ist insbesondere in der Schwangerschaft und Stillzeit angezeigt. Wir empfehlen in unserer Ambulanz zur Prävention der Therapie der Osteoporose als Basistherapie die "1000er Regel": täglich 1000 mg Calcium und 1000 IE Vitamin D(3).Vitamin D reduziert ferner das Sturzrisiko, verbessert die Muskelkraft und besitzt noch zahlreiche positive Wirkungen auf andere Organsysteme. Das Auftreten von Nierensteinen oder einer Gefässverkalkung ist bei Osteoporose-Patienten in der empfohlenen Dosis und bei normaler Flüssigkeitszufuhr nicht zu befürchten.Der Einsatz aktiver Vitamin-D-Metabolite ist auf Grund der Studiendatenlage zur Therapie der postmenopausalen Osteoporose nicht zu empfehlen und nur bei Funktionsstörungen der Leber und/oder Niere zu diskutieren. Ein unkritischer Einsatz von hydroxylierten Formen des Vitamin D bei Sturzpatienten ist auch aus Kostengründen nicht sinnvoll. Eine Substitution mit anderen Mineralien, Vitaminen oder Spurenelementen ist nur bei Vorliegen von nachgewiesenen Mangelzuständen sinnvoll und vertretbar.
In the hypotheses which was published recently [1], the author suggested that vitamin D deficiency can account for the secular trends in the prevalence of obesity and for individual differences in its onset and severity. It may be possible to reverse the increasing prevalence of obesity by improving vitamin D status. This idea is very constructive. It is well known that vitamin D and calcium is essential for bone formation, vitamin D insufficient results in osteomalacia, which is characterized by a defect in bone mineralization [2]. Nevertheless, results of other studies showed that adiposity is an important determinant of serum 25-hydroxyvitamin D and may be primarily responsible for the association between low vitamin D status [3–5]. Thus, decreasing of serum vitamin D concentration can enhance the prevalence of obesity, which supports Foss’s hypothesis. In addition, there are several studies support a role for vitamin D in other metabolic diseases. In the first, decreasing of vitamin D impairs glucose- and arginine-induced insulin secretion in perfused rat pancreas [6,7] and vitamin D supplementation improves first-phase insulin secretion in type 2 diabetic patients [8]. Secondly, vitamin D may adjust blood pressure by regulating the renin–angiotensin system [9] and there is a negative relationship between serum 1,25-dihydroxyvitamin D levels and plasma renin activity [10]. The last but not least, low circulating 25-hydroxyvitamin D levels have been noted in some patients with cardiovascular disease and dyslipidemia [11,12], and hypovitaminosis D has been associated with increased total serum cholesterol concentration [13,14]. Based on the above analyses, it can be concluded that vitamin D insufficiency is not only in association with obesity. In other words, vitamin D deficiency is a potentially significant reason, not only for obesity, but also for hypertension, insulin metabolism and dyslipidemia.
Vitamin D deficiency is associated with heightened risk of cardiovascular disease. Potential mechanisms include involvement of vitamin D in regulation of renin-angiotensin system and manufacture and secretion of cardiac natriuretic peptides. Our aim was to document relationships between 25 hydroxyvitamin [25(OH)D] and N-terminal pro B-type natriuretic peptide (NT-proBNP) and plasma renin activity (PRA) levels and to document the effect of vitamin D administration on NT-proBNP and PRA levels in vitamin D deficient subjects.
Serum 25(OH)D, parathyroid hormone (PTH), plasma or serum NT-proBNP and PRA levels were measured at baseline in nulliparous and lactating women and after 2 months of oral vitamin D2 (2,000 IU/day or 60,000 IU/month) supplementation to lactating women.
Baseline levels of 25(OH)D were low (<50 nmol/L) in most women whereas PRA and NT-proBNP levels were within the normal range. There were no significant correlations between baseline 25(OH)D or PTH with NT-proBNP and PRA. Vitamin D administration over a 2-month period in lactating women was associated with a decline in NT-proBNP (by 9.1 +/- 2.0 pmol/L; p < 0.001) and PRA (by 0.32 +/- 0.17 nmol/L/hr; p = 0.064). However, there were no significant correlations between the changes from baseline in 25(OH)D and either NT-proBNP (r = -0.04, p = 0.8) or PRA (r = -0.04, p = 0.8).
We found no significant correlations between 25(OH)D or PTH with NT-proBNP and PRA in vitamin D deficient women. Further information is required to clarify the effects of vitamin D administration on cardiac structure and function.
Racial differences in cardiovascular risk factors do not fully explain the higher prevalence of lower-extremity peripheral arterial disease (PAD) in black adults.
We sought to determine whether any of this excess risk may be explained by vitamin D status, which has been widely documented to be lower in blacks than in whites.
This population-based cross-sectional study included 2987 white and 866 black persons aged >or=40 y from the 2001-2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial pressure index of <0.90 in either leg.
Mean (+/-SEM) 25-hydroxyvitamin D [25(OH)D] concentrations were significantly lower in black than in white adults (39.2 +/- 1.0 and 63.7 +/- 1.1 nmol/L, respectively; P < 0.001). Adjusted odds ratios for PAD decreased in a dose-dependent fashion with increasing quartiles of 25(OH)D in white adults [1.00 (referent), 0.86, 0.67, and 0.53; P for trend < 0.001]. In black adults, the association was nonlinear; models with cubic splines suggested evidence of greater odds for PAD and a trend for lower odds for PAD at the lowest and highest concentrations of 25(OH)D, respectively. After adjustment for racial differences in socioeconomic status and for traditional and novel risk factors, odds for PAD in black compared with white adults were reduced from 2.11 (95% CI: 1.55, 2.87) to 1.67 (1.11, 2.51). After additional adjustment for 25(OH)D, the odds were further reduced to 1.33 (0.84, 2.10).
Racial differences in vitamin D status may explain nearly one-third of the excess risk of PAD in black compared with white adults. Additional research is needed to confirm these findings.
The identification of vitamin D receptor expression in different tissues suggests a widespread role for vitamin D action beyond its classical function in bone and mineral metabolism. Recently, the importance of vitamin D status as a risk factor in the development of metabolic syndrome has been the focus of several studies.
Pathophysiological processes in coronary artery disease (CAD) are influenced by genetic factors. Since (i) inducible nitric oxide synthase (iNOS) has important cardiovascular effects, and (ii) the promoter of the iNOS gene (NOS2A) is genetically modulated by a 4 bp insertion/deletion (j/k) polymorphism located 0.7 kb upstream, we decided to examine the influence of this variant on clinical variables in 856 CAD patients of Anglo-Celtic/Northern European extraction. We found that 2 % of CAD patients were homozygous for the j allele, and 19 % were heterozygous. Males made up 74 % of the patient group, and in these the j allele was associated with 38 % higher plasma glucose levels (P l 0.005), a 4.8 % elevation in the waist/hip ratio (P l 0.009) and a 48 % greater frequency of unstable angina (P l 0.014). The j allele, by influencing iNOS expression, could thus contribute to indices of insulin resistance and angina severity in male CAD patients.
Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy.
We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months.
The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups.
Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).
The mechanism controlling cell-specific Ang II production in the brain remains unclear despite evidence supporting neuron-specific renin and glial- and neuronal-specific angiotensinogen (AGT) expression. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II-like immunoreactivity was markedly increased in the subfornical organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGT(flox)), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGT(flox) by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRA(flox) mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.
The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca(2+) (inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-(1-7).
Macula densa cells in the distal nephron, according to the classic paradigm, are salt sensors that generate paracrine chemical signals in the juxtaglomerular apparatus to control vital kidney functions, including renal blood flow, glomerular filtration, and renin release. Renin is the rate-limiting step in the activation of the renin-angiotensin system, a key modulator of body fluid homeostasis. Here, we discuss recent advances in understanding macula densa sensing and suggest these cells, in addition to salt, also sense various chemical and metabolic signals in the tubular environment that directly trigger renin release.
We recently showed that losartan and paricalcitol are synergistic in the treatment of diabetic nephropathy in a model of type 1 diabetes. To test this strategy in a model of type 2 diabetes, we treated 2-month-old diabetic Lprdb/db mice with losartan, paricalcitol, or a combination of losartan and paricalcitol for 3 months. Vehicle-treated diabetic mice developed progressive albuminuria and glomerular abnormalities with mesangial expansion and glomerulosclerosis compared to their non-diabetic littermate control mice. Accompanying damage of the glomerular filtration barrier was a marked reduction in podocyte number as well as reduced expression of slit diaphragm proteins. Further, there was increased glomerular expression of extracellular matrix proteins, monocyte chemoattractant protein-1 and transforming growth factor-beta. Losartan or paricalcitol each alone moderately ameliorated albuminuria and glomerular damage. However, their combined use showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduced synthesis of extracellular matrix proteins, and reduction of glomerulosclerosis. These effects were accompanied by blockade of the compensatory increase of renin production and angiotensin I/II accumulation in the kidney. Thus, our study further shows that vitamin D analogs can increase the efficacy of AT1 receptor blockade, leading to a more effective prevention of kidney disease in type 2 diabetes.
Growing evidence suggests that active vitamin D slows the progression of chronic kidney diseases. Here we compared the individual renal protective efficacy of paricalcitol and trandolapril (an angiotensin-converting enzyme inhibitor) in obstructive nephropathy, and examined any potential additive effects of their combination on attenuating renal fibrosis and inflammation. Mice underwent unilateral ureteral obstruction and were treated individually with paricalcitol or trandolapril or their combination. Compared to vehicle-treated controls, monotherapy with paricalcitol or trandolapril inhibited the expression and accumulation of fibronectin and type I and type III collagen, suppressed alpha-smooth muscle actin, vimentin, and Snail1 expression, and reduced total collagen content in the obstructed kidney. Combination therapy led to a more profound inhibition of all parameters. Monotherapy also suppressed renal RANTES (regulated on activation, normal T cell expressed and secreted) and tumor necrosis factor (TNF)-alpha expression and inhibited renal infiltration of T cells and macrophages, whereas the combination had additive effects. Renin expression was induced in the fibrotic kidney and was augmented by trandolapril. Paricalcitol blocked renin induction in the absence or presence of trandolapril. Our study indicates that paricalcitol has renal protective effects, comparable to that of trandolapril, in reducing interstitial fibrosis and inflammation. Combination therapy had additive efficacy in retarding renal scar formation during obstructive nephropathy.
Previously, we showed that vitamin D receptor gene knockout leads to hyperreninemia independent of calcium metabolism; however, the contribution of parathyroid hormone to renin upregulation remained unclear. Here we separated the role of vitamin D and parathyroid hormone in the regulation of renin expression in vivo by generating transgenic mice that overexpressed the human vitamin D receptor in renin-producing cells using the 4.1 kb Ren-1c gene promoter. Targeting of human vitamin D receptor to the juxtaglomerular cells of the mice was confirmed by immunohistochemistry. Renal renin mRNA levels and plasma renin activity were decreased in these transgenic mice by about 50% and 30%, respectively, with no significant change in blood pressure, calcium, or parathyroid hormone levels. Moreover using vitamin D receptor knockout mice, we found that expression of the human receptor in their juxtaglomerular cells reduced renin expression in these mice without affecting calcium or parathyroid hormone status. Our study shows that suppression of renin expression by 1,25-dihydroxyvitamin D in vivo is independent of parathyroid hormone and calcium.
Vitamin D deficiency has been linked to cardiovascular disease and early mortality in patients on hemodialysis; however, it is not known if the same association exists at earlier stages of chronic kidney disease. To determine this we enrolled 168 consecutive new referrals to a chronic kidney disease clinic over a 2 year period and followed them for up to 6 years. All patients were clinically stable and had an estimated glomerular filtration rate (eGFR) at stage 2 or less and were without an imminent need for dialysis. Baseline 25-hydroxyvitamin D levels directly and significantly correlated with eGFR. After an average follow-up of 48 months, 48 patients started dialysis and 78 had died. In crude analyses, 25-hydroxyvitamin D predicted both time to death and end-stage renal disease. A dual-event Cox's model confirmed 25-hydroxyvitamin D as an independent predictor of study outcomes when adjusted for age, heart failure, smoking, C-reactive protein, albumin, phosphate, use of converting enzyme inhibitors or angiotensin receptor blockers, and eGFR. Our study shows that plasma 25-hydroxyvitamin D is an independent inverse predictor of disease progression and death in patients with stage 2-5 chronic kidney disease.
The renin–angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We have shown that vitamin D exerts renoprotective actions by transcriptionally suppressing renin. Here we demonstrated that combination therapy with an AT1 receptor blocker and a vitamin D analog markedly ameliorated renal injury in the streptozotocin (STZ)-induced diabetes model due to the blockade of the compensatory renin rise by the vitamin D analog, leading to more effective RAS inhibition. STZ-treated diabetic DBA/2J mice developed progressive albuminuria and glomerulosclerosis within 13 weeks, accompanied by increased intrarenal production of angiotensin (Ang) II, fibronection, TGF-β, and MCP-1 and decreased expression of slit diaphragm proteins. Treatment of the diabetic mice with losartan or paricalcitol (19-nor-1,25-dihydroxyvitamin D2, an activated vitamin D analog) alone moderately ameliorated kidney injury; however, combined treatment with losartan and paricalcitol completely prevented albuminuria, restored glomerular filtration barrier structure, and markedly reduced glomerulosclerosis. The combined treatment suppressed the induction of fibronection, TGF-β, and MCP-1 and reversed the decline of slit diaphragm proteins nephrin, Neph-1, ZO-1, and α-actinin-4. These were accompanied by blockade of intrarenal renin and Ang II accumulation induced by hyperglycemia and losartan. These data demonstrate that inhibition of the RAS with combination of vitamin D analogs and RAS inhibitors effectively prevents renal injury in diabetic nephropathy.
• albuminuria
• glomerulosclerosis
• renin–angiotensin system
The renal renin-angiotensin system plays a major role in determining the rate of chronic renal disease progression. Treatment with activators of the vitamin D receptor retards the progression of experimental chronic renal disease, and vitamin D is known to suppress the renin-angiotensin system in other organs. Here we determined if the beneficial effects of paricalcitol (19-nor 1,25-dihydroxyvitamin D(2)) were associated with suppression of renin-angiotensin gene expression in the kidney. Rats with the remnant kidney model of chronic renal failure (5/6 nephrectomy) were given two different doses of paricalcitol thrice weekly for 8 weeks. Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in the remnant kidney by 30-50 percent compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor, and vascular endothelial growth factor were all significantly decreased. Glomerular and tubulointerstitial damage, hypertension, proteinuria, and the deterioration of renal function resulting from renal ablation were all similarly and significantly improved with both treatment doses. These studies suggest that the beneficial effects of vitamin D receptor activators in experimental chronic renal failure are due, at least in part, to down-regulation of the renal renin-angiotensin system.
Many inbred strains of mice have a single locus encoding renin, Ren-1, whereas other inbred strains have two tandemly linked loci, Ren-1 and Ren-2. Each of these renin genes in inbred mice exhibits a unique pattern of tissue-specific expression. As a prerequisite to understanding the structural basis for the expression differences, we have physically characterized the sequence organization of this chromosomal region in both types of strains. Pulsed field gel electrophoresis was initially used to compare the long-range structure of this region in C57BL/6 (Ren-1) and DBA/2 (Ren-1 + Ren-2) mice. The structure in both inbred strains is extremely similar, except for an additional 30 kb containing Ren-2 in DBA/2 mice. The boundaries of the extra 30-kb segment were sequenced and compared to homologous sequences flanking the Ren-1 alleles. This analysis identified the precise recombination site, and also the presence of a large insertion, between the renin loci in DBA/2. The renin gene duplication apparently resulted from recombination between sequences sharing little homology, suggesting that nonhomologous chromosomal breakage and rejoining may have been involved mechanistically in the event.
We constructed transgenic mice containing a renin-promoter SV40 T antigen fusion transgene with the intention of inducing neoplasia in renin-expressing cells and isolating renin-expressing cell lines in vitro. We examined six kidney tumors from mice representing three different transgenic lines and found they expressed their endogenous renin gene. Initially, five nonclonal kidney tumor-derived cell lines were established which expressed their endogenous renin gene in addition to the transgene. They retained active renin intracellularly and constitutively secreted an inactive form of renin (prorenin). One of these cell lines was cloned to homogeneity. This line maintained high level expression of renin mRNA throughout 3 months of continuous culture. Although the cells contained an equal proportion of active and inactive renin, the species constitutively secreted into the media was predominantly (95%) prorenin. However, active renin secretion was stimulated 2.3- and 4.6-fold by treatment with 8-bromo-cAMP after 4 and 15 h, respectively. In addition, the presence of multiple secretory granules was confirmed by ultrastructural analysis. These cells, which express renin mRNA and can regulate secretion of active renin, should provide an excellent tool for studying renin gene regulation and secretion. Furthermore, these mice should provide a useful source for the establishment of renin-expressing cell lines from a variety of renin-expressing tissues.
Although angiotensin II (Ang II)-forming enzymatic activity in the human left cardiac ventricle is minimally inhibited by angiotensin I (Ang I) converting enzyme inhibitors, over 75% of this activity is inhibited by serine proteinase inhibitors (Urata, H., Healy, B., Stewart, R. W., Bumpus, F. M., and Husain, A. (1990) Circ. Res. 66, 883-890). We now report the identification and characterization of the major Ang II-forming, neutral serine proteinase, from left ventricular tissues of the human heart. A 115,150-fold purification from human cardiac membranes yielded a purified protein with an Mr of 30,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Based upon its amino-terminal sequence, the major human cardiac Ang II-forming proteinase appears to be a novel member of the chymase subfamily of chymotrypsin-like serine proteinases. Human heart chymase was completely inhibited by the serine proteinase inhibitors, soybean trypsin inhibitor, phenylmethylsulfonyl fluoride, and chymostatin. It was partially inhibited by p-tosyl-L-phenylalanine chloromethyl ketone, but was not inhibited by p-tosyl-L-lysine chloromethyl ketone, and aprotinin. Also, human heart chymase was not inhibited by inhibitors of the other three classes of proteinases. Human heart chymase has a high specificity for the conversion of Ang I to Ang II and the Ang I-carboxyl-terminal dipeptide His-Leu (Km = 60 microM; Kcat = 11,900 min-1; Kcat/Km = 198 min-1 microM-1). Human heart chymase did not degrade several peptide hormones, including Ang II, bradykinin, and vasoactive intestinal peptide, nor did it form Ang II from angiotensinogen. The high substrate specificity of human heart chymase for Ang I distinguishes it from other Ang II-forming enzymes including Ang I converting enzyme, tonin, kallikrein, cathepsin G, and other known chymases.
The angiotensin substrate analog Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys has no significant effect on blood pressure in sodium-replete monkeys (Macaca fascicularis) but blocks the pressor response to infused human renin. Pressor responses to angiotensin I and angiotensin II are not attenuated. In five studies in sodium-depleted monkeys, an infusion of 2 mg of the peptide per kg of body weight resulted in a reduction of mean arterial pressure (MAP) from 105 +/- 4 to 79 +/- 3 mm Hg, which is not significantly different from the response to 1 mg of the angiotensin I-converting enzyme inhibitor teprotide per kg. In uninephrectomized monkeys, inflation of a suprarenal aortic cuff caused an increase in MAP from 107 +/- 3 to 131 +/- 3 mm Hg. Infusion of 0.6 mg of the renin-inhibitory peptide per kg was followed by a return of blood pressure to 107 +/- 4 mm Hg--a depressor response similar to that observed with teprotide. This specific in vivo inhibitor of renin can now be applied to a wide variety of physiologic studies.
Angiotensin (AT) II, the bioactive octapeptide in the renin-angiotensin system that plays a key role in cardiovascular homeostasis,
exerts its multiple effects through the different types of AT receptors, AT1a, AT1b, and AT2. Previously, we showed chronic
hypotension in angiotensinogen (the precursor of AT)-deficient mice and a dramatic increase in renin mRNA levels in its kidney,
but it remains unclear which types of AT receptors regulate the blood pressure and renin gene expression. In order to elucidate
the physiological roles of AT1a receptor, we generated mutant mice with a targeted replacement of the AT1a receptor loci by
the lacZ gene. In the heterozygous mutant mice, the strong lacZ staining was found in the glomerulus and juxtaglomerular apparatus of the renal cortex, which coincided with that of the
signals detected by in situ hybridization. Chronic hypotension was observed in the heterozygous and homozygous mutant mice, with 10 and 22 mm Hg lower
systolic blood pressure, respectively, than that of wild-type littermates. Both the levels of renin mRNA in the kidney and
plasma renin activity were markedly increased only in the homozygous mutant mice. These results demonstrated that an AT1a-mediated
signal transduction pathway is, at least in part, involved in the regulation of blood pressure and renin gene expression.
The renin-angiotensin system is a major determinant of arterial pressure and volume homeostasis in mammals through the actions of angiotensin II, the proteolytic digestion product of angiotensinogen. Molecular genetic studies in several human populations have revealed genetic linkage between the angiotensinogen gene and both hypertension and increased plasma angiotensinogen. Transgenic mice were generated with a human angiotensinogen genomic clone to develop an animal model to examine tissue- and cell-specific expression of the gene and to determine if overexpression of angiotensinogen results in hypertension. Human angiotensinogen mRNA was expressed in transgenic mouse liver, kidney, heart, adrenal gland, ovary, brain, and white and brown adipose tissue and, in kidney, was exclusively localized to epithelial cells of the proximal convoluted tubules. Plasma levels of human angiotensinogen were approximately 150-fold higher in transgenic mice than that found normally in human plasma. The blood pressure of mice bearing the human angiotensinogen gene was normal but infusion of a single bolus dose of purified human renin resulted in a transient increase in blood pressure of approximately 30 mm Hg within 2 min. These results suggest that abnormalities in the angiotensinogen gene resulting in increased circulating levels of angiotensinogen could potentially contribute in part to the pathogenesis of essential hypertension.
1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorption rather than receptor deficiency, mineral ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum ionized calcium levels in the VDR-ablated mice. The correction of ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalization of mineral ion homeostasis can prev...
In this report, we demonstrate a significant inverse correlation between contractility and serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] levels and no correlation between contractility and serum levels of calcium, phosphate, or PTH. We also examined myosin isozyme distribution in vitamin D3-deficient rats, because myosin isozyme distribution can alter contractility. There was a significant increase in the levels of the V1 myosin isozyme in animals raised on a vitamin D3-deficient diet that maintained normal serum calcium and phosphate levels. There was no difference in the relative myosin isozyme distribution in animals raised on a hypocalcemia-yielding vitamin D3-deficient diet vs. animals raised on a control diet. As increased contractility has been observed in both groups of vitamin D3-deficient animals, a shift in myosin isozyme distribution cannot solely explain the increase in contractility previously observed in the vitamin D3-deficient rat heart. To determine whether 1,25-(OH)2D3 directly regulates myosin isozyme levels, we analyzed myosin isozyme distribution in primary cultures of ventricular myocytes. We found that 1,25-(OH)2D3 reduces total myosin levels, but does not alter myosin isozyme distribution. Thus, we show that the influence of vitamin D3 status on myosin isozyme expression in the intact rat involves a complex regulatory system of direct and indirect effects.
To determine the association of skin color, measured by a reflectometer, with blood pressure in US blacks, we studied a community sample of 457 blacks from three US cities. Persons taking antihypertensive medications were excluded. Both systolic and diastolic blood pressure were higher in darker persons and increased by 2 mm Hg for every 1-SD increase in skin darkness. However, the association was dependent on socioeconomic status, whether measured by education or an index consisting of education, occupation, and ethnicity, being present only in persons with lower levels of either indicator. Using multiple linear regression, both systolic and diastolic blood pressure remained significantly associated with darker skin color in the lower levels of socioeconomic status, independent of age, body mass index, and concentrations of blood glucose, serum urea nitrogen, serum uric acid, and urinary sodium and potassium. The association of skin color with blood pressure only in low socioeconomic strata may be due to the lesser ability of such groups to deal with the psychosocial stress associated with darker skin color. However, these findings also are consistent with an interaction between an environmental factor associated with low socioeconomic status and a susceptible gene that has a higher prevalence in persons with darker skin color.
(JAMA. 1991;265:599-602)
PRIMARY hypertension is a polygenic condition in which blood pressure is enigmatically elevated; it remains a leading cause of cardiovascular disease and death due to cerebral haemorrhage, cardiac failure and kidney disease. The genes for several of the proteins involved in blood pressure homeostasis have been cloned and characterized1-8, including those of the renin-angiotensin system, which plays a central part in blood pressure control9-10. Here we describe the introduction of the mouse Ren-2 renin gene3,11-13 into the genome of the rat and demonstrate that expression of this gene causes severe hypertension. These trans-genic animals represent a model for hypertension in which the genetic basis for the disease is known. Further, as the transgenic animals do not overexpress active renin in the kidney and have low levels of active renin in their plasma, they also provide a new model for low-renin hypertension.
1,25-Dihydroxy vitamin D3[1,25(OH)2D3] an active form of vitamin D, has roles in many biological phenomena such as calcium homeostasis and bone formation1−3, which are thought to be mediated by the 1,25(OH)2D3 receptor (VDR), a member of the nuclear hormone receptor superfamily4−6. However, the molecular basis for the actions of 1,25(OH)2D3 in bone formation, its role during development and VDR genetic polymorphisms for predicting bone mineral density7 are uncertain. To investigate the functional role of VDR, we generated mice deficient in VDR by gene targeting. We report here that in VDR null mutant mice, no defects in development and growth were observed before weaning, irrespective of reduced expression of vitamin D target genes. After weaning, however, mutants failed to thrive, with appearance of alopoecia, hypocalcaemia and infertility, and bone formation was severely impaired as a typical feature of vitamin D−dependent rickets type II (refs 8,9). Unlike humans with this disease, most of the null mutant mice died within 15 weeks after birth, and uterine hypoplasia with impaired folliculogenesis was found in female reproductive organs. These defects, such as alopoecia and uterine hypoplasia, were not observed in vitamin D−deficient animals. The findings establish a critical role for VDR in growth, bone formation and female reproduction in the post-weaning stage.
This study aimed to characterize the influence of endogenous angiotensin II on renal renin gene expression during different
states of a stimulated and of a suppressed renin system. To this end the renin system in male Sprague Dawley rats was stimulated
by unilateral renal artery clipping (0.2 mm clip), by furosemide (60 mg/kg per diem) or isoproterenol (160 μg/kg per diem),
and by ingestion of a low-salt diet (0.02%), or was suppressed by setting a contralateral renal artery clip (0.2-mm clip)
or by ingestion of a high-salt diet (4%). During the last 2 days of these different treatment regimens, the animals were treated
with the angiotensin II AT1 receptor antagonist losartan (40 mg/kg per diem) and renal renin mRNA levels were assayed. Renin
gene expression was stimulated four- to fivefold by renal artery clipping and isoproterenol infusion, two- to threefold by
furosemide and a low-salt diet, and about fourfold by losartan. Additional treatment with losartan potentiated the stimulatory
effects of a low-salt diet, of furosemide and of isoproterenol infusion on renin gene expression, whilst there was no significant
additional effect of losartan on renin gene expression in clipped kidneys. Both contralateral renal artery clipping and a
high-salt diet decreased renin mRNA levels to about 50% of the control value. In rats with a unilateral clip, additional losartan
treatment caused renin mRNA to increase to about 350% of the control value in the contralateral kidney but to only 110% of
the control value in animals on a high-salt diet. These findings suggest that the enhanced formation of angiotensin II during
a low-salt intake, during tubular inhibition of salt reabsorption or during β-adrenoreceptor activation plays a relevant negative
feedback role in the activation of the renin gene. Moreover, in rats with one hypoperfused kidney, angiotensin II could be
involved in the inhibition of renin gene expression in the contralateral kidney. In hypoperfused kidneys, however, and in
animals on a high-salt diet, angiotensin II appears to play only a minor feedback role in the regulation of the renin gene.
The aim of the study was to assess the incidence and clinical implications of increased plasma angiotensin II despite chronic ACE inhibitor therapy in patients with heart failure.
The studied population consisted of 70 patients (mean age 59+/-9 years). Plasma renin activity and plasma concentration of aldosterone, norepinephrine, atrial natriuretic peptide, angiotensin II, tumour necrosis factor, interleukin-6 and interleukin-1B were assessed at 6 months of ACE inhibitor therapy. Mean left ventricular ejection fraction was 24+/-5% and the end-systolic and end-diastolic diameters were 59+/-9 and 71+/-8 mm, respectively. Despite chronic enalapril or captopril therapy, 35 patients (50%) had increased plasma angiotensin II (median 33 pg. ml(-1), range 17-84), while it was in the normal range in the remaining 35 patients (median 10 pg. ml(-1), range 5-15). Plasma renin activity (P=0.005), interleukin-6 (P=0.004), New York Heart Association functional class III-IV (P=0. 006), furosemide dose (P=0.01), lack of beta-blocker therapy (P=0. 04) and norepinephrine (P=0.04) were univariately associated with increased angiotensin II. Multivariate regression analysis identified the plasma renin activity (0.0004), norepinephrine (0.02) and interleukin-6 (0.03) as independent predictors of plasma angiotensin II. During follow-up (35+/-29 months), nine (12.8%) patients died and 13 had new heart failure episodes. Increased plasma angiotensin II, despite ACE inhibitor therapy, was a significant predictor of death or heart failure according to the Kaplan-Meier survival method by log rank test (P=0.002).
Fifty per cent of patients with heart failure, ha increased plasma angiotension II despite chronic ACE inhibitor therapy. These patients had higher neurohormonal activation and poor prognosis.
Vitamin D inhibits renin expression and blocks the compensatory induction of renin associated with the use of renin-angiotensin system inhibitors. Here we test the therapeutic effects of two commonly used vitamin D analogs and their combination with losartan on the development of left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle, losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol for 2 months. Blood pressure was markedly reduced by losartan, but not by paricalcitol or doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy and almost complete prevention of left ventricular hypertrophy with the combination therapies. Attenuation of cardiac and cardiomyocyte hypertrophy, and suppression of atrial and brain natriuretic peptides, were most marked in the combination therapy groups. These changes were well correlated with left ventricular gene and microRNA expression profiles in the different treatment groups. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. The same vitamin D analogs suppressed plasma renin activity in patients receiving chronic hemodialysis. These data demonstrate that vitamin D analogs have potent antihypertrophic activity in part via suppression of renin in the kidney and heart, and combination of these analogs with losartan achieves much better therapeutic effects because of the blockade of the compensatory renin increase.
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.
Analogs of vitamin D attenuate renal injury in several models of kidney disease, but the mechanism underlying this renoprotective effect is unknown. To address the role of the vitamin D receptor (VDR) in renal fibrogenesis, we subjected VDR-null mice to unilateral ureteral obstruction for 7 days. Compared with wild-type mice, VDR-null mice developed more severe renal damage in the obstructed kidney, with marked tubular atrophy and interstitial fibrosis. Significant induction of extracellular matrix proteins (fibronectin and collagen I), profibrogenic and proinflammatory factors (TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein 1), and epithelial-to-mesenchymal transition accompanied this histologic damage. Because VDR ablation activates the renin-angiotensin system and leads to accumulation of angiotensin II (AngII) in the kidney, we assessed whether elevated AngII in the VDR-null kidney promotes injury. Treatment with the angiotensin type 1 antagonist losartan eliminated the difference in obstruction-induced interstitial fibrosis between wild-type and VDR-null mice, suggesting that AngII contributes to the enhanced renal fibrosis observed in obstructed VDR-null kidneys. Taken together, these results suggest that the VDR attenuates obstructive renal injury at least in part by suppressing the renin-angiotensin system.
Vitamin D regulates the renin-angiotensin system (RAS) in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the RAS in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II (Ang II) and the renal plasma flow response to infused Ang II, which is an indirect measure of the intrinsic RAS activity in the kidney. Compared with individuals with sufficient 25-hydroxyvitamin D levels (> or = 30.0 ng/mL), those with insufficiency (15.0 to 29.9 ng/mL) and deficiency (<15.0 ng/mL) had higher circulating Ang II levels (P for trend=0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused Ang II (mean decrease of 115 mL/min per 1.73 m(2) in renal plasma flow versus 145 mL/min per 1.73 m(2) among those with sufficient vitamin D levels; P for trend=0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy humans.
The intrarenal renin-angiotensin system (RAS) plays a key role in the development of diabetic nephropathy. Recently, we showed that combination therapy with an AT(1) receptor blocker (ARB) and an activated vitamin D analog produced excellent synergistic effects against diabetic nephropathy, as a result of blockade of the ARB-induced compensatory renin increase. Given the diversity of vitamin D analogs, here we used a pro-drug vitamin D analog, doxercalciferol (1alpha-hydroxyvitamin D(2)), to further test the efficacy of the combination strategy in long-term treatment. Streptozotocin-induced diabetic DBA/2J mice were treated with vehicle, losartan, doxercalciferol (0.4 and 0.6 microg/kg), or losartan and doxercalciferol combinations for 20 wk. Vehicle-treated diabetic mice developed progressive albuminuria and glomerulosclerosis. Losartan alone moderately ameliorated kidney injury, with renin being drastically upregulated. A similar therapeutic effect was seen with doxercalciferol alone, which markedly suppressed renin and angiotensinogen expression. The losartan and doxercalciferol combination most effectively prevented albuminuria, restored glomerular filtration barrier structure, and dramatically reduced glomerulosclerosis in a dose-dependent manner. These effects were accompanied by blockade of intrarenal renin upregulation and ANG II accumulation. These data demonstrate an excellent therapeutic potential for doxercalciferol in diabetic renal disease and confirm the concept that blockade of the compensatory renin increase enhances the efficacy of RAS inhibition and produces synergistic therapeutic effects in combination therapy.
Vitamin D receptor (VDR)-null mice develop polyuria, but the underlying mechanism remains unknown. In this study, we investigated the relationship between vitamin D and homeostasis of water and electrolytes. VDR-null mice had polyuria, but the urine osmolarity was normal as a result of high salt excretion. The urinary responses to water restriction and to vasopressin were similar between wild-type and VDR-null mice, suggesting intact fluid-handling capacity in VDR-null mice. Compared with wild-type mice, however, renin and angiotensin II were dramatically upregulated in the kidney and brain of VDR-null mice, leading to a marked increase in water intake and salt appetite. Angiotensin II-mediated upregulation of intestinal NHE3 expression partially explained the increased salt absorption and excretion in VDR-null mice. In the brain of VDR-null mice, expression of c-Fos, which is known to associate with increased water intake, was increased in the hypothalamic paraventricular nucleus and the subfornical organ. Treatment with an angiotensin II type 1 receptor antagonist normalized water intake, urinary volume, and c-Fos expression in VDR-null mice. Furthermore, despite a salt-deficient diet to reduce intestinal salt absorption, VDR-null mice still maintained the increased water intake and urinary output. Together, these data indicate that the polyuria observed in VDR-null mice is not caused by impaired renal fluid handling or increased intestinal salt absorption but rather is the result of increased water intake induced by the increase in systemic and brain angiotensin II.
The renin substrate analog His-Pro-Phe-His-Leu-D-Leu-Val-Tyr ([D-Leu6]-octapeptide) acts as a potent inhibitor of renin because of the D-amino acid substitution at the cleavage site. This inhibitor was coupled to CNBr-activated Sepharose 4B to yield a support for affinity chromatography. Hog renin with a specific activity of 1.2 Goldblatt units/mg was in one step purified 195-fold to a final specific activity of 234 Goldblatt units/mg. Application of a pH gradient from 5.0 to 7.5 to the support was found to be the most successful elution program, probably because the [D-Leu6]-octapeptide is not an inhibitor for renin at neutral pH.
Census areas in Detroit were ranked for their stress scores based on instability (e.g., crime, marital break up) and socioeconomic status. Four areas were selected for detailed study: 1) high stress, population predominantly black, 2) white, 3) low stress, population predominantly black, 4) white. A sample was drawn from each area of persons of the predominant race, 25-60 years old, married and living with spouse, and having relatives in the Detroit Area. Nurses interviewed such persons; three blood pressure readings were taken during the first half-hour of medical history, and skin color was rated. Results show that darker skin color, for black males especially, is related to higher pressure, independently of nine control variables (e.g., age, weight, socioeconomic status, etc.). However, younger black males (25-39 years of age) in high stress areas had higher pressure than counterparts in low stress areas, regardless of skin color and relative weight; for older black males (40-59 years of age) darker skin color was correlated with higher pressure, regardless of relative weight or stress area. For 35 blacks whose fathers were from the West Indies, pressures were higher than those with American-born fathers. These findings suggest that varied gene mixtures may be related to blood pressure levels and that skin color, an indicator of possible metabolic significance, combines with socially induced stress to induce higher blood pressures in lower class American blacks.
It has long been known that the renin-angiotensin system plays an integral role in the regulation of blood pressure and electrolyte and fluid balance in mammals. The advent of molecular biologic techniques has afforded new insights into the genes regulating blood pressure. Laboratory mice and rats have been used as experimental models to examine the structural organization and expression of the renin gene. It is now well established that some mice, unlike rats and humans, contain a duplicated copy of the renin locus, which accounts for the high level of renin activity long known to be found in the submandibular gland of some mice. Indeed it is this fortuitous observation that facilitated the isolation of the first complementary DNA clones for renin and ultimately the many species-specific probes now available to analyze mammalian tissues for evidence of primary renin expression. The use of complementary DNAs as probes for primary renin expression helped confirm and further clarify earlier studies demonstrating the presence of renin activity in a number of extrarenal tissues. Although expression in some of these tissues is evolutionarily conserved, their significance has still been elusive. In this report we review the impact of molecular biology on our current understanding of renin gene structure and organization, tissue- and cell-specific expression and regulation, and the changes in renin expression throughout ontogeny. In addition, we describe how new developments in gene transfer technology have added important tools to our arsenal for examining renin gene regulation and how these technologies can be used to develop new tools for renin and hypertension research.
To determine the association of skin color, measured by a reflectometer, with blood pressure in US blacks, we studied a community sample of 457 blacks from three US cities. Persons taking antihypertensive medications were excluded. Both systolic and diastolic blood pressure were higher in darker persons and increased by 2 mm Hg for every 1-SD increase in skin darkness. However, the association was dependent on socioeconomic status, whether measured by education or an index consisting of education, occupation, and ethnicity, being present only in person with lower levels of either indicator. Using multiple linear regression, both systolic and diastolic blood pressure remained significantly associated with darker skin color in the lower levels of socioeconomic status, independent of age, body mass index, and concentrations of blood glucose, serum urea nitrogen, serum uric acid, and urinary sodium and potassium. The association of skin color with blood pressure only in low socioeconomic strata may be due to the lesser ability of such groups to deal with the psychosocial stress associated with darker skin color. However, these findings also are consistent with an interaction between an environmental factor associated with low socioeconomic status and a susceptible gene that has a higher prevalence in persons with darker skin color.
To assess the influence of environmental temperature on blood pressure, we analyzed 42,813 readings of systolic and diastolic
blood pressures in recumbent and upright positions in 2,000 hypertensive patients in our clinic in correlation to noon temperature
and mean daily temperature in Montréal. The sample comprised 860 men and 1140 women with an average age of 55 years. Analysis
of variance showed highly statistically significant negative correlations for all blood pressure values between different
noon temperature, as well as mean daily temperature, groups. The greatest difference for systolic blood pressure was 7 mm
Hg, and for diastolic blood pressure it was 3 mm Hg, within the – 24 °C to 27°C temperature range. The same relationship between
blood pressure and different environmental temperatures was also seen when the blood pressure recordings were divided between
temperature below 0°C and above 0°C, ie, within the winter or summer months. This environmental effect may have a clinically
significant impact because thermosensitivity appears to be related to hypertension Am J Hypertens 1991;4:422-426
Renin secretion by the kidney is inhibited by an increase in free intracellular calcium concentration. This increase in free intracellular calcium content may be augmented by serum 1,25-dihydroxyvitamin D. In 10 subjects with high renin hypertension, an increase in dietary sodium intake resulted in an increase in urinary calcium excretion (2.5 to 3.4 mmol/L, P = .011) and an increase in serum 1,25-dihydroxyvitamin D (51.2 to 61.0 pmol/L, P = .045). An inverse correlation existed between the change in vitamin D and the change in plasma renin activity (r = -0.765, P = .01). An inverse correlation also existed between the change in plasma renin activity and the change in mean arterial blood pressure (r = -0.757, P = .011). It is postulated that the increase in dietary sodium led to an increase in serum 1,25-dihydroxyvitamin D concentration, which may have contributed to an increase in intracellular calcium concentration, a decrease in renal secretion of renin, and a fall in plasma renin activity. The resultant fall in PRA in part effected the change in blood pressure to the increased sodium intake. Therefore, 1,25-dihydroxyvitamin D may be a mediator in the response of high renin hypertension to increased sodium intake.
Fetuses were examined to produce a developmental profile of renin expression in the kidneys and adrenal glands in single renin gene and two renin gene strains of mice. Sites of renin expression were detected by in situ hybridization using an 35S-labeled antisense RNA probe complimentary to the renin cDNA. Accumulation of renin transcripts in the adrenal gland reached a maximum at 15.5 days post coitum for all strains examined, but declined to undetectable levels by birth in one gene strains, while in two gene strains, the levels of renin transcripts lessened and by birth became limited to the developing inner cortex. Kidney renin transcripts were first detected at 14.5 days post coitum in the newly developing arteries in fetuses of both genotypes of mice. As the renal arterial tree developed, renin mRNA containing cells were progressively localized to more distal blood vessels and finally to the specialized cells of the afferent arteriole (juxtaglomerular cells). These results were confirmed by examining the localization of immunoreactive T antigen in transgenic fetuses. These mice carried a transgene which placed the SV40 T antigen structural gene under control of renin regulatory elements. Expression of T antigen occurred at the same sites in the kidneys and adrenal glands as renin mRNA. Furthermore, in strains with two renin genes, primer extension analysis indicated transcripts from both genes were present in equal proportion in combined kidney and adrenal gland extracts of total RNA. These transcripts were full length in size. The transient localization of renin mRNA in cells of the fetal intrarenal arteries is consistent with the notion that renin may be a useful marker for the developing renal vasculature.
The x-ray crystal structure of recombinant human renin has been determined. Molecular dynamics techniques that included crystallographic data as a restraint were used to improve an initial model based on porcine pepsinogen. The present agreement factor for data from 8.0 to 2.5 angstroms (A) is 0.236. Some of the surface loops are poorly determined, and these disordered regions border a 30 A wide solvent channel. Comparison of renin with other aspartyl proteinases shows that, although the structural cores and active sites are highly conserved, surface residues, some of which are critical for specificity, vary greatly (up to 10A). Knowledge of the actual structure, as opposed to the use of models based on related enzymes, should facilitate the design of renin inhibitors.
Patients with essential hypertension, in particular those with low plasma renin activity (PRA), are reported to have lowered plasma-ionized calcium and elevated parathyroid hormone levels. In this study 1 microgram alphacalcidol (1 alpha-hydroxy-vitamin D3) was given in a double-blind, placebo-controlled fashion over four months to 39 subjects with mild to moderate hypertension. There was a significant rise in PRA in the treatment group when compared to placebo (P less than .05), but the mean blood pressure response was similar in the two groups. When the treatment group was divided according to pretreatment PRA it was, however, seen that subjects with low PRA displayed a reduction in diastolic blood pressure, whereas those with high PRA raised their blood pressure compared to placebo. Also subjects with low pretreatment values for plasma-ionized calcium and high levels of parathyroid hormone showed a reduction in diastolic blood pressure. This study supports the idea of a relationship between calcium metabolism and the renin-aldosterone system in essential hypertension and describes a beneficial effect of vitamin D supplementation on blood pressure in low-renin hypertension.
The N-terminal sequences of human and canine angiotensinogen and two hybrid sequences were synthesized and used to determine whether the species specificity of renin is influenced by amino-acid residues adjacent to the cleavage site. kcat/Km for the generation of angiotensin I from the N-terminal tridecapeptide of human angiotensinogen by canine renin is 0.37% of that observed when the N-terminal tetradecapeptide from canine angiotensinogen is used as a substrate. Replacement of the valine residue at P'1 in the human tridecapeptide with the leucine residue from the canine sequence triples kcat and improves Km 4-fold. Replacement of isoleucine residue at P'2 with the valine residue from the canine sequence enhances Km 8-fold. Substitution of the histidine residue at P'3 with the tyrosine serine sequence of canine angiotensinogen increases kcat an order of magnitude. Results obtained with the synthetic substrate are similar to those observed with the protein substrates. Canine renin does not cleave human angiotensinogen. Also, kcat/Km of canine renin for its homologous substrate is about 6-times greater than the kcat/Km value for human renin acting on human angiotensinogen.
An in vitro method has been used to examine whether secretion of renin from the juxtaglomerular apparatus is affected by changes in the sodium chloride concentration of the tubular fluid at the macula densa. Single juxtaglomerular apparatuses were microdissected from rabbits and the tubule segment containing the macula densa was perfused, while simultaneously the entire juxtaglomerular apparatus was superfused, and the fluid was collected for renin measurement. In this preparation, in which influences from renal nerves and local hemodynamic effects are eliminated, a decrease in the tubular sodium chloride concentration at the macula densa results in a prompt stimulation of the renin release rate.
Elevated plasma renin activity (PRA) has been documented in patients with established acute renal failure. To study the association of PRA and renal dysfunction, 53 patients who were at risk of developing acute renal failure had serial measurements of PRA, renal function, and urinary beta 2-microglobulin. Those entered for study had pneumonia, septicaemia, volume loss with hypotension, or major surgical procedures with complications. Patients were divided into groups of abnormal or normal renal function. Abnormal renal function was defined by an elevated plasma urea and/or creatinine level with a submaximal urine urea to plasma urea ratio. The mean values of PRA for the abnormal and normal renal function groups, respectively, were 29 and 5.2 ng/ml/h (p less than 0.0001) and for beta 2-microglobulin 16.2 and 6.4 micrograms/l X 10(3) (p less than 0.0005). A linear regression of the logs of PRA to beta 2-microglobulin for the total group of patients gave an r value of 0.526 (p less than 0.001). These data show an association of PRA to renal dysfunction and tubular injury/dysfunction in the prerenal phase of renal failure, suggesting an effect of the renin-angiotensin system at this phase. It is not possible, however, to conclude from our study that the renin-angiotensin system has a direct role in the development of established acute tubular necrosis, since only 3 patients fell within this category.
Circulating levels of the calcium-regulating hormones, calcitonin, calcitriol, and parathyroid hormone, were analyzed in relation to plasma renin activity in 10 persons with normal blood pressure and in 51 persons with essential hypertension. Calcitriol (p less than 0.008) and parathyroid hormone (p less than 0.01) levels were elevated in hypertensives with low renin activity, whereas calcitonin levels were higher in patients with high renin activity (p less than 0.008), compared with normotensive controls and other hypertensive patients. Continuous relationships were observed between calcitriol levels and plasma renin activity in all patients (r = -0.65, p less than 0.001) and between parathyroid hormone levels and urinary sodium excretion in hypertensive patients with low renin activity (r = -0.63, p less than 0.01). Together, these results support a linkage between calcium metabolism and renin-sodium factors in essential hypertension. Calcium-regulating hormones and the renin-aldosterone system may coordinately mediate the blood pressure effects of differing dietary calcium and sodium intakes at the cellular level by altering cellular handling of monovalent and divalent ions.
Intravenous infusion of angiotensin II (6.3-200 ng/kg min) inhibited renin secretion in dogs under conditions of basal or elevated renin secretion. This inhibition was independent of changes in mean renal arterial blood pressure. We propose a negative feedback effect of circulating angiotensin on renin secretion.
Dietary strontium inhibits both the synthesis of 1,25-dihydroxycholecalciferol and intestinal calcium absorption in vitamin
D3-repleted chicks. 1,25-Dihydroxycholecalciferol restores calcium absorption to normal, while 25-hydroxycholecalciferol is
without effect in the strontium-fed chick. It is suggested that strontium induces rickets by blocking the biosynthesis of
1,25-dihydroxycholecalciferol, the metabolically active form of vitamin D in the intestine.
Stroke is a major cause of death in the People's Republic of China (PRC), and the geographic distribution of stroke death varies substantially. We conducted an ecological analysis to investigate the relationship of prevalence of hypertension and other risk factors with stroke incidence and mortality in the PRC.
The relationship between prevalence of risk factors and stroke incidence and mortality in the PRC was assessed in 29 provinces by examining risk factor data from PRC national surveys and incidence and mortality from the 1986 PRC National Stroke Study.
A highly statistically significant correlation between prevalence of hypertension and stroke incidence (r = .838, P < .001) and mortality (r = .841, P < .001) was observed. Prevalence of hypertension explained over 70% of the geographic variability in stroke incidence (partial R2 = .703) and mortality (partial R2 = .707) in the PRC. There was a north-south gradient, with a higher prevalence of hypertension and stroke incidence and mortality in the north compared with the south of the country. In multiple Poisson regression analysis, a 10% increase in the prevalence of hypertension was associated with a 2.80-fold higher incidence and 2.68-fold higher mortality from stroke, whereas a 10% increase in the prevalence of alcohol consumption was associated with a 29% higher incidence and a 16% higher mortality from stroke. A 10% increase in the prevalence of cigarette smoking was associated with a 19% higher mortality from stroke.
In the PRC, the prevalence of hypertension is strongly associated with the risk of stroke, and the geographic variation in stroke incidence and mortality is due mainly to differences in the prevalence of hypertension.
A possible role for vitamin D deficiency in contributing to the winter increase in cardiovascular disease mortality was investigated by testing the effect of vitamin D supplementation on blood pressure and other cardiovascular risk factors during winter.
Randomised double-blind trial of vitamin D supplementation in winter.
Men and women, mean age 70 years (range 63-76) recruited from general practitioner age-sex registers in Cambridge (UK).
95 people received a single oral dose of 2.5 mg cholecalciferol and 94 received the placebo at baseline interviews during December 1991. Follow-up assessment was 5 weeks later during January 1992.
Comparing follow-up with baseline assessment, serum 25-hydroxyvitamin D increased in the treated group and decreased slightly in the placebo group [mean (s.d.) change: 7.2 (+/- 3.8) vs -1.4 (+/- 1.1) ng/ml, P = 0.0001]; while parathyroid hormone decreased in the treated, and increased in the placebo, group [-0.27 (+/- 0.78) vs 0.13 (+/- 0.75) pmol/l, P = 0.0004]. However, the mean change in blood pressure was similar in both groups: systolic -5 (+/- 13) vs -5 (+/- 16) mmHg, P = 0.81; diastolic -1 (+/- 9) vs -1 (+/- 9), P = 0.92; as was the mean change in serum cholesterol [-0.07 (+/- 0.52) vs -0.05 (+/- 0.60) mmol/l, P = 0.81]. In contrast, the mean change in radial pulse was significantly decreased in the treated group compared with placebo [-2 (+/- 9) vs 1 (+/- 7) beats per min, P = 0.030].
The failure of vitamin D supplementation to change blood pressure or serum cholesterol suggests that the winter increase in these factors is not caused by decreased vitamin D levels.
The renin-angiotensin system (RAS) is the most important regulator of electrolyte homeostasis and blood pressure. Our recently generated transgenic mice carrying either the human renin (hREN) or human angiotensinogen (hANG) genes did not develop hypertension but dual gene strains obtained by cross-mating separate lines of mice exhibited a chronically sustained increase in blood pressure, suggesting the presence of species-specific reactivity between renin and angiotensinogen. In order to examine this specificity, the present study was designed to perform a strictly comparative study on hydrolysis of hANG by hREN and mouse submandibular renin (mREN) in vitro by using pure proteins. The recombinant hANG (rhANG) and the synthetic human-type tridecapeptide (hTDP), Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His, corresponding to the N-terminal sequences of hANG, were used to determine the species specificity of recombinant hREN (rhREN) and mREN. While hTDP was cleaved by both rhREN and mREN with similar Km and with the same order of kcat, rhANG was cleaved by mREN with 16.7-fold higher Km and with 28.2-fold lower kcat than by rhREN. These results showed that kcat/Km value of mREN for rhANG was 468-fold lower than that for rhREN acting on rhANG.