Aldosterone System and Calcium-Regulatory Hormones

REVIEW The renin–angiotensin–aldosterone system and calcium-regulatory hormones

A Vaidya1,2,3, JM Brown3 and JS Williams2,3

There is increasing evidence of a clinically relevant interplay between the renin–angiotensin–aldosterone system and calcium- regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis, while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Speciﬁcally, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies and provide insight into the results of prior and ongoing intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent.

Journal of Human Hypertension (2015) 29, 515–521; doi:10.1038/jhh.2014.125; published online 29 January 2015

INTRODUCTION THE RAAS AND CALCIUM The renin–angiotensin–aldosterone system (RAAS) has a crucial Calcium dysregulation has been implicated as a potential role in the physiologic regulation of sodium and potassium mechanism for negative cardiovascular outcomes.16–21 Acute balance, intravascular volume and blood pressure.1 It is now also hypercalcemia increases blood pressure in normal, healthy well established that excess RAAS activity increases cardiovascular humans.22–25 Elevated serum calcium concentrations increase disease risk that can be mitigated by inhibiting or blocking the cardiovascular risk as demonstrated in multiple large epidemio- RAAS.2,3 logic studies.16,18,20,21 Calciﬁcation of large arteries, coronary Parathyroid hormone (PTH) and vitamin D are calcium- arteries, and the microvasculature have all been associated with regulatory hormones that have a crucial role in skeletal poor cardiovascular outcomes.16,18,21 The role of calcium in – health.4 6 PTH has several key roles, including (1) raising regulating the RAAS may represent an important mechanistic circulating calcium by mobilizing calcium from skeletal reservoirs; contribution in these observations. (2) promoting the 1-α-hydroxylation of 25-hydroxyvitamin D (25(OH)D); (3) indirectly increasing intestinal calcium absorption (via vitamin D receptor (VDR) activation); (4) and increasing renal Acute renin secretion is under inhibitory control via several calcium absorption. Elevations in circulating calcium, in turn, calcium-mediated processes negatively regulate PTH and synthesis of 1,25-dihydroxyvitamin D Calcium cation is universally relevant in signal transduction, (1.25(OH)2D). In addition to these known physiologic roles of PTH enzyme activation and membrane potential in virtually all and vitamin D, high PTH and low vitamin D have been repeatedly mammalian tissues.26 As such, both intra- and extracellular associated with cardiovascular disease and mortality,7–15 although calcium concentrations are under tight regulatory control. It is consistent and conclusive evidence from intervention studies to not surprising, therefore, that a dependent relationship must exist support these observations have yet to be reported. between calcium homeostasis and the RAAS. Perhaps, the most This review highlights emerging interactions between calcium widely and detailed descriptions are the interactions of calcium and calcium-regulatory hormones with the RAAS that may and renin secretion by the juxtaglomerular and renal arteriolar describe novel endocrine relationships and/or may represent cells.27–31 In contrast to almost all other interactions involving mechanistic explanations for the links between calcium-regulatory calcium-mediated signaling, in the case of renin release increasing hormones and cardiovascular diseases. calcium concentrations has an inhibitory effect. Renin secretion is

1Center for Adrenal Disorders, Harvard Medical School, Boston, MA, USA; 2Division of Endocrinology, Diabetes, and Hypertension, Harvard Medical School, Boston, MA, USA and 3Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Correspondence: Dr JS Williams, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA or Dr A Vaidya, Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA. E-mail: [email protected] or [email protected] Received 28 September 2014; revised 1 December 2014; accepted 9 December 2014; published online 29 January 2015 RAAS and calcium-regulatory hormones A Vaidya et al 516 mainly dependent on cyclic AMP formation. Cyclic AMP availability with aldosterone-producing adenomas when compared with is the net effect of positive adenylyl cyclase activity and bilateral adrenal hyperplasia, suggesting that the severity of competing degradative activity of calmodulin-activated aldosteronism correlated with the severity of hyperparathyroid- phosphodiesterase.30,32–39 Increasing intracellular calcium concen- ism. Among observational studies that have evaluated the impact trations decrease net cyclic AMP formation by dampening of primary aldosteronism on PTH levels following either surgical adenylate cyclase and enhancing phosphodiesterase activities. (adrenalectomy) or pharmacologic (mineralocorticoid receptor Extracellular concentrations of calcium affect intracellular antagonism) therapy, both surgery and medical therapy have concentrations via the calcium-sensing receptor present on renal demonstrated reductions in PTH that parallel the treatment of – juxtaglomerular cells.39–42 Stimulation of the calcium-sensing primary aldosteronism.54 57 receptor with the calcimimetic cinacalcet results in a marked The health implications of hyperparathyroidism in primary decrease in cyclic AMP formation and renin secretion.41 Mobiliza- aldosteronism may be significant—beyond the known cardiovas- tion of cytosolic calcium in the juxtaglomerular can occur via cular risks associated with primary aldosteronism, a concomitant activation of L-type voltage-gated calcium channels or release state of hyperparathyroidism could contribute to skeletal diseases from intracellular calcium stores via membrane action potentials.43 (such as osteoporosis and fracture) and compound cardiovascular The exact signal-transduction pathway in the juxtaglomerular risk since elevated PTH has also been associated with cardiovas- apparatus is as yet unknown, but likely similar to that of calcium- cular disease and mortality.7,8 Animal studies58,59 and several sensing receptor in parathyroid cells.44–46 human observational studies in primary aldosteronism have supported the concern that primary aldosteronism may result in declines in bone mineral density and an increased risk for fracture. In vivo, acute activation of calcium-sensing receptor inhibits renin 60 release Salcuni et al. demonstrated that patients with primary aldoster- – onism had higher PTH levels and lower bone mineral density In vivo studies of calcium renin interaction are similar to those when compared with hypertensive controls. In this study, primary described in vitro. Acutely raising circulating plasma calcium aldosteronism was associated with a higher odds for osteoporosis concentration is mostly associated with inhibiting renin release (odds ratio (OR) = 15.4 (1.83–130)) and vertebral fractures with a signal that is more clearly visible under renin-stimulated – 41,47 (OR = 30.4 (1.07 862)), although the sample sizes evaluated were conditions such as low dietary salt intake. Pharmacologically small, as reflected by the wide 95% confidence intervals for the stimulating the calcium-sensing receptor decreases renin secre- observed point estimates.60 Despite this limitation, among the tion and antagonizing it prevents the inhibitory effects of 40,41 subset treated with surgery or mineralocorticoid receptor hypercalcemia on renin release. antagonists, PTH levels were observed to decline and bone density observed to rise, suggesting that primary aldosteronism, Clinically, chronic activation of calcium-sensing receptor is hyperparathyroidism, decreased bone density and vertebral associated with elevated plasma renin activity fracture may all be potentially linked in a causal pathway. Similar 61 Curiously, chronically stimulated calcium-sensing receptor is most findings were also independently seen by Ceccoli et al. and 62 often associated with higher plasma renin activity. Primary Petramala et al. These human observations have implicated hyperparathyroidism has been associated mostly with elevated hyperaldosteronism as a potentially treatable cause of low bone plasma renin activity,48 although not always.49 Maximally density that may result in clinical fragility fractures and have stimulated calcium-sensing receptor as seen in Type V Bartter’s further supported elevated PTH as a mediator of this effect. 50 fl However, further studies are needed to determine whether syndrome results in hyperreninemia. Thus, apparently con ict- 63 ing results may have more to do with the degree of calcium- aldosterone acts directly on bone, whether aldosterone induces sensing receptor activation under pathophysiologic states, and a hyperparathyroidism that results in bone remodeling or whether the ability to detect plasma renin activity differences under normal targeting aldosterone in a large clinical trial results in improved dietary sodium conditions. skeletal health. Overall, acute elevation of calcium inhibits renin release via The connection between hyperaldosteronism and skeletal several extra-, and in turn, intracellular mechanisms. States of disease is not restricted to primary aldosteronism and has been chronic calcium elevation, or activation of the calcium-sensing observed in conditions of secondary hyperaldosteronism such as – receptor, are associated with variable elevation in plasma renin heart failure and chronic kidney disease. In a case control study activity. It is not known to what extent these clinical observations consisting of 167 patients with heart failure and non-traumatic are due to secondary (indirect) activation of plasma renin activity. fractures and 668 age-matched control patients without fracture, Carbone et al.64 found that the use of spironolactone was associated with a reduced odds of fracture (OR = 0.575 THE RAAS AND PTH (0.346–0.955)). Hassan et al.17 reported that among a population of 950 patients with chronic kidney disease, those prescribed Growing evidence points to a bidirectional and positive relation- fi ship between the RAAS and PTH.51,52 Basic studies, observational spironolactone had signi cantly lower PTH after taking the studies and a few intervention studies have now reported on this medication and a lower risk of hospitalization for heart failure novel two-way interaction between the RAAS and PTH that may when compared with patients with chronic kidney disease not prescribed spironolactone (hazard ratio = 0.37 (0.19–0.74)). Koiwa have clinical implications with respect to mechanisms of human 65 cardiovascular and skeletal disease. et al. evaluated a cohort of patients with chronic kidney disease and observed that the use of any renin–angiotensin–aldosterone inhibitors was associated with significantly lower PTH levels.65 fl In uence of the RAAS on PTH Given that both primary aldosteronism and secondary forms of Studies in primary aldosteronism have repeatedly observed a link hyperaldosteronism have been linked with hyperparathyroidism between excess aldosterone and hyperparathyroidism. Resnick and skeletal disease, which appear to be mitigated with the and Laragh53 described high PTH levels and a negative calcium treatment of the underlying hyperaldosteronism, what mechan- balance in a small cohort of subjects with primary aldosteronism; isms might explain these observed phenomena? Some have this finding was again observed by other investigators evaluating speculated that aldosterone may exert a direct stimulatory – larger cohorts with primary aldosteronism,54 57 raising speculation influence on the parathyroid gland to induce PTH secretion, as that aldosterone could directly stimulate PTH secretion. Rossi the mineralocorticoid receptor has been found to be expressed in et al.57 showed that PTH levels were significantly higher in patients parathyroid glands.66,67 A number of case reports have described

Journal of Human Hypertension (2015) 515 – 521 © 2015 Macmillan Publishers Limited RAAS and calcium-regulatory hormones A Vaidya et al 517 the concomitant development of primary hyperparathyroidism suggesting that the phenotype of hyperaldosteronism and with primary aldosteronism, suggesting that aldosterone may possibly the chronicity of elevated aldosterone exposure may have a role in the pathogenesis of hyperparathyroidism.66,68 influence PTH elevations.74 Alternatively, or perhaps in addition, aldosterone may indirectly stimulate PTH secretion by acting on the nephron to induce Influence of PTH on the RAAS hypercalciuria and subsequent hypocalcemia (secondary hyper- Increased PTH has been associated with vascular dysfunction and parathyroidism).54,55,61,69,70 cardiovascular outcomes;7,8,75,76 however, the mechanisms under- Mechanistic studies to evaluate the physiologic relationship lying this association remain unclear. In addition to the influence between the RAAS and PTH have been reported in subjects 71 of the RAAS on PTH, several lines of evidence support a direct without primary aldosteronism. Grant et al. initially demon- effect of PTH on components of the RAAS, which in turn may strated that a dose-dependent relationship between angiotensin II 51,77 and PTH existed in studies where healthy humans were infused explain the link between PTH and cardiovascular disease. with exogenous angiotensin II. Brown et al.67 and Vaidya et al.72 Basic laboratory studies have shown that PTH enhances extended this experiment and confirmed that an acute infusion of aldosterone secretion from human adrenocortical cells in vitro by acting on PTH receptors present on zona glomerulosa cells, and exogenous angiotensin II to healthy humans increased PTH (and 78,79 aldosterone) in a dose-dependent manner within 1–2 h. Further, that antagonists of the PTH receptor block this effect. In small treatment with the angiotensin-converting enzyme inhibitor intervention studies, infusions of exogenous PTH-like peptides – have resulted in increases in adrenal aldosterone secretion and captopril acutely lowered PTH (by 10 12% from baseline), in 80 addition to lowering angiotensin II and aldosterone concentra- urinary tetrahydroaldosterone excretion, and also increases in plasma renin activity.71 In vitro studies describe similar stimulation tions. This was in contrast to infusion of aldosterone, which did 81,82 not acutely affect PTH levels. However, in a randomized placebo- of renin by PTH, suggesting that PTH may enhance the controlled trial, healthy subjects without primary aldosteronism activity of the RAAS via multiple methods. Patients with primary treated with spironolactone 50 mg daily for 6 weeks to block hyperparathyroidism (P-HPT) have been shown to demonstrate a fi heightened aldosterone secretory response to an infusion of aldosterone effect displayed signi cant lowering of PTH levels 83 with concomitant increases in serum calcium, whereas subjects angiotensin II, and in at least three well-documented reports, 67 patients with P-HPT have developed concomitant primary assigned to placebo did not. These results suggest that in the 66,68,84 acute setting, angiotensin II may exert a stimulatory effect on PTH aldosteronism. In some of these cases, surgical parathyroidectomy resulted in cure of the aldosteronism, providing that can be mitigated by lowering angiotensin II with an 84 angiotensin-converting enzyme inhibitor; however, acute tantalizing evidence as to cause and effect. In contrast, some fi increases in aldosterone do not appreciably alter PTH. In contrast, observational studies have been unable to nd any difference in RAAS components between those with P-HPT and controls in the chronic setting aldosterone may increase PTH, and this 85 effect may be mitigated by a mineralocorticoid antagonist— without P-HPT, underscoring the need for more dedicated and observations that were similar to those reported in the prospective study designs to evaluate this relationship. aforementioned cohorts of subjects with primary aldosteronism. 67 Thus, this study by Brown et al. provides evidence implicating THE RAAS AND VITAMIN D multiple RAAS components interacting with PTH, and a differential The conversion of 25(OH)D to the active metabolite and VDR temporal effect dictating their relationships. In assessments of 4 parathyroid pathology, both normal and adenomatous para- agonist 1,25(OH)2D is a process governed by PTH, yet vitamin D thyroid tissue have been shown to express the angiotensin type 1 may have independent influences on the RAAS. Low vitamin D receptor and the mineralocorticoid receptor, and the expression status has been associated with clinical outcomes that are also of these receptors was three- to fourfold greater among traditionally associated with excess RAAS activity, including 13–15,86 adenomatous tissue, giving further support to direct actions of hypertension, inflammation and cardiovascular disease. angiotensin II and/or aldosterone on the parathyroid.67 Animal studies and human genetic association studies have Most recently, large-scale epidemiologic studies have added the provided mechanistic support for these observations; however, greatest support for the aforementioned findings from small conflicting data exist, and there is a strong need for large-scale observational and intervention studies. In a cross-sectional randomized studies to confirm the influence of vitamin D therapy analysis of more than 3000 participants, Fischer et al.73 showed on the RAAS and RAAS-mediated clinical outcomes. – that participants with an aldosterone-to-renin ratio that was Animal studies (mice) have shown that the 1,25(OH)2D VDR greater than the 90th percentile (suggestive of a ‘primary complex negatively regulates renin expression, and that this aldosteronism-like’ phenotype) had higher PTH levels than those vitamin D-induced reduction in RAAS activity can prevent adverse vascular outcomes to a similar extent induced by pharmacologic with an aldosterone-to-renin ratio that was less than the 90th – percentile.73 Similarly, among 41500 community-based partici- angiotensin receptor antagonism.15,87 93 Human studies have pants without known hyperparathyroidism or primary aldosteron- supported this theory, demonstrating that low circulating vitamin ism from the Multi-Ethnic Study of Atherosclerosis, Brown et al.74 D concentrations are associated with higher plasma renin activity showed that higher serum aldosterone levels were significantly and angiotensin II concentrations,86,94,95 and that vitamin D associated with higher serum PTH levels (+4.5 pg ml − 1 per +1 deficiency is associated with higher RAAS activity that can be − 1 72,94,96 ng dl of aldosterone after multivariable adjustments), and that lowered following intervention with vitamin D3 therapy. the use of RAAS inhibitor medications was associated with lower Extrapolation of these results suggests that vitamin D therapy PTH levels when compared with the use of non-RAAS inhibitor might serve to lower RAAS activity and improve complications antihypertensive medications (−2.0 pg ml − 1 after multivariable associated with excess RAAS activity such as hypertension, adjustments). In fact, of all potential antihypertensive therapies, nephropathy and insulin resistance.15 the use of RAAS inhibitors associated with the lowest PTH. This To date, there have been mostly unimpressive or negative study also observed that patients with the highest PTH values results from human interventional studies. Many human vitamin D were those who had high serum aldosterone levels and low renin intervention studies have focused on blood pressure or albumi- activity (a ‘primary aldosteronism-like’ phenotype). In contrast, nuria as primary outcomes, and as both of these outcomes are those with a secondary aldosteronism-like phenotype (high renin related to excessive RAAS activity, these studies are particularly activity and high aldosterone) displayed PTH levels that were no interesting to the topic of this review. One recent randomized different from participants with low or normal aldosterone levels, study showed that reasonably high doses of vitamin D3 therapy

© 2015 Macmillan Publishers Limited Journal of Human Hypertension (2015) 515 – 521 RAAS and calcium-regulatory hormones A Vaidya et al 518 over 3 months modestly lowered systolic blood pressure in includes several important players, each requiring metabolism and blacks.9 In addition, morbidly obese individuals with vitamin D regulation at different steps. One factor complicating this deficiency have been reported to have modest reductions in physiologic relationship is the fact that 25(OH)D has low affinity mean arterial pressure following 1 month of very high-dose for the VDR when compared with 1,25(OH)2D, yet most vitamin D vitamin D3 therapy, and this phenomenon was associated with interventions in research and clinical settings use vitamin D3 to reductions in the local vascular-tissue renin–angiotensin system.72 raise 25(OH)D levels. However, the continued conversion to the 97 98 99 Larsen et al., de Zeeuw et al. and Joergensen et al. have active VDR agonist 1,25(OH)2D by sheer substrate abundance may shown that paracalcitol therapy, a VDR agonist, can lower be downregulated depending on other pertinent variables. For albuminuria in advanced chronic kidney disease with or without example, with high-dose vitamin D3 therapy that increases serum diabetes; however, whether this effect is attributable to RAAS calcium and 1,25(OH)2D, PTH is physiologically downregulated 14,97–99 activity reduction remains to be proved. and therefore the synthesis of 1,25(OH)2D and dietary calcium In contrast, a number of well-conducted intervention studies absorption are reduced. In this scenario, normal physiology have found no effect of vitamin D therapy on blood pressure. ‘buffers’ the effect of sustained and chronic vitamin D3 Recently, Scragg et al.100 and Witham et al.,101 in combination with supplementation until the elevations in 25(OH)D exceed this several other small and short-term vitamin D3 intervention buffering capacity and create a substrate-driven PTH-independent 13,14 studies, have mostly reported no blood pressure-lowering augmentation of 1,25(OH)2D. Although circulating concentrations effect associated with vitamin D3 therapy for time durations of 1 of these vitamin D metabolites may correlate with or dictate year and longer. Perhaps, the most notable vitamin D3 interven- downstream biologic effect, it is well recognized that binding tion study to examine blood pressure-lowering effects to date is protein concentrations and genetic polymorphisms in the the DAYLIGHT study. In this double-blinded, randomized, multi- infrastructure governing this pathway has crucial roles in center trial, including 534 individuals with stage I hypertension, interindividual responses to vitamin D therapy. Powe et al.104 fi 4000 IU of daily vitamin D3 for 6 months did not affect the mean demonstrated that black Americans had signi cantly lower 25(OH) 24-h systolic blood pressure (primary end point) when compared D and vitamin D-binding protein concentrations when compared with 400 IU of daily vitamin D .102 with white Americans; however, they had similar bioavailable 25 3 105 These contradictory human intervention studies raise doubt (OH)D concentrations as a result. This study points out a major about the consistency of observations, or at a minimum, the weakness in the reliance on a circulating blood level of 25(OH)D to relevance of vitamin D therapy related to blood pressure-lowering determine vitamin D status and correlations with downstream and cardiovascular outcomes. At the very least, it can be biologic activity. In most research studies that assess vitamin D concluded that vitamin D3 therapy in durations of 3–12 months interventions, the assessment of binding protein concentrations, does not markedly lower blood pressure akin to pharmacologic bioavailable 25(OH)D or 1,25(OH)2D, to assess active metabolite antihypertensives; however, long-term studies are lacking. It levels, is not performed or considered. should be noted that except for the DAYLIGHT study, none of Similarly, the influence of genetic polymorphisms in the these studies was particularly large, and on the same token none metabolism and activity of the vitamin D system has been shown of these studies (including the DAYLIGHT study) were particularly to have an important role, particularly in mediating vitamin long in duration; therefore, larger and longer population-based D-RAAS interactions; almost every step of vitamin D metabolism 106,107 interventional studies with more refined effect detection will be has been shown to be modified by genetic variation. The needed to determine satisfactorily whether vitamin D therapies FokI polymorphism within the VDR has been shown to be a fi functional variant that alters the length and activity of the 1,25 can de nitively modulate clinical outcomes related to excessive 108,109 (OH)2D–VDR complex. Genetic variation at FokI has been RAAS activity. Perhaps, the best candidate for such a large study is 110–112 the currently ongoing VITAL study.103 associated with hypertension and has been shown to predict plasma renin activity in both normotensives and Beyond large and longer trials, it is important to remember and 113 consider that ‘vitamin D’ is not a single metabolite, rather is hypertensives. Further, the combination of 25(OH)D concentra- colloquially used to refer to a complex hormone system that tions and FokI genotype enhances the prediction of renin activity in hypertension, suggesting important pharmacogenetic consid- erations when evaluating the impact of vitamin D interventions to raise 25(OH)D or influence a clinical RAAS-mediated outcome.113 This is best exemplified in the large prospective study evaluating the influence of vitamin D status on composite cardiovascular, skeletal and cancer outcomes in the Cardiovascular Health Study.114 In this study, more than 1500 participants were followed for more than 10 years, and an analysis to evaluate whether 25 (OH)D deficiency in combination with genetic variation predicted the composite outcomes. The outcome when VDR genotype was not accounted for.108 In contrast, when the authors stratified their clinical outcomes by VDR genotype, they observed significant risk modification that was dependent on genotype, further supporting the important pharmocogenetic interplay that underlies the Figure 1. Interactions between the RAAS and calcium-regulatory relationship between vitamin D and clinical outcomes.114 Whether hormones. The 1,25(OH)2D–VDR complex, and calcium ion, can the RAAS has a mediating role in these relationships was decrease plasma renin activity by either decreasing renin expression not assessed in this study, but should be strongly considered or renin secretion, respectively. Some evidence has shown that PTH when evaluating future study designs given the supportive may directly increase renin secretion in the acute setting. preclinical data. Aldosterone and angiotensin II stimulate the secretion of PTH via the MR and AT1R; the former with chronic exposure, whereas the latter in the acute setting. PTH, in turn, has been implicated as an CONCLUSION aldosterone secretagogue via interactions with the PTH-R in the adrenal zona glomerulosa. ACE, angiotensin-converting enzyme; In summary, growing evidence suggests interactions between AT1R, angiotensin receptor type 1; Ca2+, calcium cation; CaSR, calcium-regulatory hormones and the RAAS with potentially calcium-sensing receptor; MR, mineralocorticoid receptor. important clinical implications. Calcium and vitamin D have been

Journal of Human Hypertension (2015) 515 – 521 © 2015 Macmillan Publishers Limited RAAS and calcium-regulatory hormones A Vaidya et al 519 shown to inhibit renin secretion and expression, whereas a 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally bidirectional and stimulatory relationship between PTH and representative NHANES. J Clin Endocrinol Metab 2013; 98(7): 3001–3009. aldosterone (and possibly angiotensin II) has been observed 11 Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG et al. (Figure 1). With this mounting evidence, new questions are raised Vitamin D supplementation for prevention of mortality in adults. Cochrane 1 that may have notable implications for future clinical outcomes Database Syst Rev 2014; : CD007470. 12 Durup D, Jorgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. research. Does inhibition of the RAAS or antagonism of the A reverse J-shaped association of all-cause mortality with serum mineralocorticoid receptor induce clinically relevant PTH reduc- 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab tions? And if so, are skeletal outcomes such as bone density and 2012; 97(8): 2644–2652. fragility fracture influenced by pharmacotherapies that target the 13 Vaidya A, Forman JP. Vitamin D and hypertension: current evidence and future 56 – RAAS? Does the administration of vitamin D3 or direct agonism of directions. Hypertension 2010; (5): 774 779. 14 Vaidya A, Forman JP. The future of vitamin D in vascular disease: reviewing the the VDR with 1,25(OH)2D result in clinically relevant reductions in the activity of the RAAS? And if so, are cardiovascular outcomes role of vitamin D in hypertension and kidney disease. Curr Hypertens Rep 2012; fi 14(2): 111–119. modi able with vitamin D therapies? Contemplating the inter- 15 Vaidya A, Williams JS. The relationship between vitamin D and the active complexity of two highly evolved regulatory systems is renin–angiotensin system in the pathophysiology of hypertension, kidney daunting, yet deciphering these relationships might clarify disease, and diabetes. Metabolism 2012; 61(4): 450–458. variability in outcomes research and inform the design of future 16 Foley RN, Collins AJ, Ishani A, Kalra PA. Calcium-phosphate levels and cardio- intervention studies. This in turn may provide the basis for vascular disease in community-dwelling adults: the Atherosclerosis Risk in endocrine pleiotropy in human disease management. However, Communities (ARIC) Study. Am Heart J 2008; 156(3): 556–563. interventional, prospective, well-designed human studies are 17 Hassan M, Qureshi W, Sroujieh LS, Albashaireh D, BouMalham S, Liroff M et al. severely lacking. A realignment of resources and talents will be Interplay of parathyroid hormone and aldosterone antagonist in prevention of heart failure hospitalizations in chronic kidney disease. J Renin-Angiotensin- required to move the overabundance of epidemiological associa- Aldosterone Syst 2014; 15(3): 278–285. tion observations to the critical proof of concept stage and 18 Jorde R, Sundsfjord J, Fitzgerald P, Bonaa KH. Serum calcium and cardiovascular beyond. risk factors and diseases: the Tromso Study. Hypertension 1999; 34(3): 484–490. 19 Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone levels predict coronary heart disease: the Tromso Study. Eur J Cardiovasc Prev Rehabil 2004; 11 CONFLICT OF INTEREST (1): 69–74. The authors declare no conflict of interest. 20 Larsson TE, Olauson H, Hagstrom E, Ingelsson E, Arnlov J, Lind L et al. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler Thromb Vasc Biol ACKNOWLEDGEMENTS 2010; 30(2): 333–339. 21 Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S. Serum calcium: a new, The work in this publication was supported by the National Heart, Lung and independent, prospective risk factor for myocardial infarction in middle-aged Blood Institute of the National Institutes of Health under award numbers: K23 men followed for 18 years. J Clin Epidemiol 1997; 50(8): 967–973. HL11177 (to AV). Research was also supported by a Brigham and Women’s Hospital 22 Bianchetti MG, Beretta-Piccoli C, Weidmann P, Link L, Boehringer K, Ferrier C Biomedical Research Institute Grant (to AV), a William Randolph Hearst Young et al. Calcium and blood pressure regulation in normal and hypertensive Investigator Award from the Brigham and Women’s Hospital Department of Medicine subjects. Hypertension 1983; 5(4, Part 2): Ii57–Ii65. (to AV) and a Harvard Medical School Research Fellowship (to JMB). The content is 23 Gennari C, Nami R, Bianchini C, Aversa AM. Blood pressure effects of acute fi solely the responsibility of the authors and does not necessarily represent the of cial hypercalcemia in normal subjects and thyroparathyroidectomized patients. views of the National Center for Research Resources or the National Institutes of Miner Electrolyte Metab 1985; 11(6): 369–373. Health. 24 Kamycheva E, Jorde R, Haug E, Sager G, Sundsfjord J. Effects of acute hyper- calcaemia on blood pressure in subjects with and without parathyroid hormone secretion. Acta Physiol Scand 2005; 184(2): 113–119. REFERENCES 25 Marone C, Beretta-Piccoli C, Weidmann P. Acute hypercalcemic hypertension in 1 Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body man: role of hemodynamics, catecholamines, and renin. Kidney Int 1981; 20(1): sodium-volume content (V) and renin–angiotensin (R) vasoconstriction to long- 92–96. term blood pressure. Am J Hypertens 2011; 24(11): 1164–1180. 26 Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium 2 Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al. The effect of signalling. Nat Rev Mol Cell Biol 2000; 1(1): 11–21. spironolactone on morbidity and mortality in patients with severe heart failure. 27 Atchison DK, Beierwaltes WH. The influence of extracellular and intracellular Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341 calcium on the secretion of renin. Pflugers Archiv 2013; 465(1): 59–69. (10): 709–717. 28 Friis UG, Madsen K, Stubbe J, Hansen PB, Svenningsen P, Bie P et al. Regulation 3 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an of renin secretion by renal juxtaglomerular cells. Pflugers Archiv 2013; 465(1): angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in 25–37. high-risk patients. The Heart Outcomes Prevention Evaluation Study Investiga- 29 Kotchen TA, Guthrie GP Jr.. Effects of calcium on renin and aldosterone. Am J tors. N Engl J Med 2000; 342(3): 145–153. Cardiol 1988; 62(11): 41g–46gg. 4 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266–281. 30 Macgriff S, Woo RE, Ortiz-Capisano MC, Atchison DK, Beierwaltes WH. Recruited 5 Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ. Primary hyperparathyroidism: renin-containing renal microvascular cells demonstrate the calcium paradox new concepts in clinical, densitometric and biochemical features. J Intern Med regulatory phenotype. Integr Blood Pressure Control 2014; 7:9–17. 2005; 257(1): 6–17. 31 Park CS, Malvin RL. Calcium in the control of renin release. Am J Physiol 1978; 235 6 Silverberg SJ. Vitamin D deficiency and primary hyperparathyroidism. J Bone (1): F22–F25. Miner Res 2007; 22(Suppl 2): V100–V104. 32 Facemire CS, Nguyen M, Jania L, Beierwaltes WH, Kim HS, Koller BH et al. A major 7 van Ballegooijen AJ, Reinders I, Visser M, Dekker JM, Nijpels G, Stehouwer CD role for the EP4 receptor in regulation of renin. Am J Physiol Renal Physiol 2011; et al. Serum parathyroid hormone in relation to all-cause and cardiovascular 301(5): F1035–F1041. mortality: the Hoorn study. J Clin Endocrinol Metab 2013; 98: E638–E645. 33 Friis UG, Jensen BL, Sethi S, Andreasen D, Hansen PB, Skott O. Control of renin 8 Pilz S, Tomaschitz A, Drechsler C, Ritz E, Boehm BO, Grammer TB et al. secretion from rat juxtaglomerular cells by cAMP-specific phosphodiesterases. Parathyroid hormone level is associated with mortality and cardiovascular Circ Res 2002; 90(9): 996–1003. events in patients undergoing coronary angiography. Eur Heart J 2010; 31(13): 34 Friis UG, Stubbe J, Uhrenholt TR, Svenningsen P, Nusing RM, Skott O et al. 1591–1598. Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent 9 Forman JP, Scott JB, Ng K, Drake BF, Suarez EG, Hayden DL et al. Effect of vitamin hyperpolarization and exocytosis of renin in juxtaglomerular cells. Am J Physiol D supplementation on blood pressure in blacks. Hypertension 2013; 61(4): Renal Physiol 2005; 289(5): F989–F997. 779–785. 35 Kurtz A, Pfeilschifter J, Hutter A, Buhrle C, Nobiling R, Taugner R et al. Role of 10 Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA, Looker AC, protein kinase C in inhibition of renin release caused by vasoconstrictors. Am J Schleicher RL et al. Is there a reverse J-shaped association between Physiol 1986; 250(4, Part 1): C563–C571.

© 2015 Macmillan Publishers Limited Journal of Human Hypertension (2015) 515 – 521 RAAS and calcium-regulatory hormones A Vaidya et al 520 36 Ortiz-Capisano MC, Liao TD, Ortiz PA, Beierwaltes WH. Calcium-dependent 61 Ceccoli L, Ronconi V, Giovannini L, Marcheggiani M, Turchi F, Boscaro M et al. phosphodiesterase 1C inhibits renin release from isolated juxtaglomerular cells. Bone health and aldosterone excess. Osteoporos Int 2013; 24(11): 2801–2807. Am J Physiol Regul Integr Comp Physiol 2009; 297(5): R1469–R1476. 62 Petramala L, Zinnamosca L, Settevendemmie A, Marinelli C, Nardi M, Concistre A 37 Ortiz-Capisano MC, Ortiz PA, Harding P, Garvin JL, Beierwaltes WH. Adenylyl et al. Bone and mineral metabolism in patients with primary aldosteronism. Int J cyclase isoform v mediates renin release from juxtaglomerular cells. Hypertension Endocrinol 2014; 2014: 836529. 2007; 49(3): 618–624. 63 Beavan S, Horner A, Bord S, Ireland D, Compston J. Colocalization of gluco- 38 Ortiz-Capisano MC, Ortiz PA, Harding P, Garvin JL, Beierwaltes WH. Decreased corticoid and mineralocorticoid receptors in human bone. J Bone Miner Res 2001; intracellular calcium stimulates renin release via calcium-inhibitable adenylyl 16(8): 1496–1504. cyclase. Hypertension 2007; 49(1): 162–169. 64 Carbone LD, Cross JD, Raza SH, Bush AJ, Sepanski RJ, Dhawan S et al. Fracture risk 39 Ortiz-Capisano MC, Reddy M, Mendez M, Garvin JL, Beierwaltes WH. in men with congestive heart failure risk reduction with spironolactone. JAm Juxtaglomerular cell CaSR stimulation decreases renin release via activation of Coll Cardiol 2008; 52(2): 135–138. the PLC/IP(3) pathway and the ryanodine receptor. Am J Physiol Renal Physiol 65 Koiwa F, Komukai D, Hirose M, Yoshimura A, Ando R, Sakaguchi T et al. Influence 2013; 304(3): F248–F256. of renin–angiotensin system on serum parathyroid hormone levels in uremic 40 Atchison DK, Harding P, Beierwaltes WH. Hypercalcemia reduces plasma renin patients. Clin Exp Nephrol 2012; 16(1): 130–135. via parathyroid hormone, renal interstitial calcium, and the calcium-sensing 66 Maniero C, Fassina A, Guzzardo V, Lenzini L, Amadori G, Pelizzo MR et al. Primary receptor. Hypertension 2011; 58(4): 604–610. hyperparathyroidism with concurrent primary aldosteronism. Hypertension 2011; 41 Atchison DK, Ortiz-Capisano MC, Beierwaltes WH. Acute activation of the 58(3): 341–346. calcium-sensing receptor inhibits plasma renin activity in vivo. Am J Physiol Regul 67 Brown JM, Williams JS, Luther JM, Garg R, Garza AE, Pojoga LH et al. Human Integr Compar Physiol 2010; 299(4): R1020–R1026. interventions to characterize novel relationships between the renin–angio- 42 Ortiz-Capisano MC, Ortiz PA, Garvin JL, Harding P, Beierwaltes WH. Expression tensin–aldosterone system and parathyroid hormone. Hypertension 2014; 63(2): and function of the calcium-sensing receptor in juxtaglomerular cells. Hyper- 273–280. tension 2007; 50(4): 737–743. 68 Chau K, Holmes D, Melck A, Chan-Yan C. Secondary hypertension due to con- 43 Friis UG, Jorgensen F, Andreasen D, Jensen BL, Skott O. Membrane potential and comitant aldosterone-producing adenoma and parathyroid adenoma. Am J cation channels in rat juxtaglomerular cells. Acta Physiol Scand 2004; 181(4): Hypertens (e-pub ahead of print 20 June 2014). 391–396. 69 Rastegar A, Agus Z, Connor TB, Goldberg M. Renal handling of calcium and 44 Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O et al. Cloning and phosphate during mineralocorticoid ‘escape’ in man. Kidney Int 1972; 2(5): characterization of an extracellular Ca(2+)-sensing receptor from bovine para- 279–286. thyroid. Nature 1993; 366(6455): 575–580. 70 Rossi E, Perazzoli F, Negro A, Sani C, Davoli S, Dotti C et al. Acute effects of 45 Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium intravenous sodium chloride load on calcium metabolism and on parathyroid signaling. Physiol Rev 2001; 81(1): 239–297. function in patients with primary aldosteronism compared with subjects with 46 Riccardi D, Park J, Lee WS, Gamba G, Brown EM, Hebert SC. Cloning and func- essential hypertension. Am J Hypertens 1998; 11(1, Part 1): 8–13. tional expression of a rat kidney extracellular calcium/polyvalent cation-sensing 71 Grant FD, Mandel SJ, Brown EM, Williams GH, Seely EW. Interrelationships receptor. Proc Natl Acad Sci USA 1995; 92(1): 131–135. between the renin-angiotensin-aldosterone and calcium homeostatic systems. J 47 Isaac R, Raymond JP, Rainfray M, Ardaillou R. Effects of an acute calcium load on Clin Endocrinol Metab 1992; 75(4): 988–992. plasma ACTH, cortisol, aldosterone and renin activity in man. Acta Endocrinol 72 Vaidya A, Sun B, Larson C, Forman JP, Williams JS. Vitamin D3 therapy corrects 1984; 105(2): 251–257. the tissue sensitivity to angiotensin II akin to the action of a converting enzyme 48 Richards AM, Espiner EA, Nicholls MG, Ikram H, Hamilton EJ, Maslowski AH. inhibitor in obese hypertensives: An Interventional Study. J Clin Endocrinol Metab Hormone, calcium and blood pressure relationships in primary hyperparathyr- 2012; 97(7): 2456–2465. oidism. J Hypertens 1988; 6(9): 747–752. 73 Fischer E, Hannemann A, Rettig R, Lieb W, Nauck M, Pallauf A et al. A High 49 Valvo E, Bedogna V, Gammaro L, Casagrande P, Ortalda V, Maschio G. Systemic aldosterone-to-renin ratio is associated with high serum parathyroid hormone hemodynamic pattern in primary hyperparathyroidism and its changes after concentrations in the general population. J Clin Endocrinol Metab 2014; 99(3): parathyroidectomy. Miner Electrolyte Metab 1991; 17(3): 147–152. 965–971. 50 Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R et al. 74 Brown JM, de Boer IH, Robinson-Cohen C, Kestenbaum B, Siscovick DAllison MA Association between activating mutations of calcium-sensing receptor and et al. Aldosterone, parathyroid hormone, and the use of renin-angiotensin- Bartter's syndrome. Lancet 2002; 360(9334): 692–694. aldosterone system inhibitors: the multi-ethnic study of atherosclerosis. J Clin 51 Tomaschitz A, Ritz E, Pieske B, Rus-Machan J, Kienreich K, Verheyen N et al. Endocrinol Metab (e-pub ahead of print 20 November 2014). Aldosterone and parathyroid hormone interactions as mediators of metabolic 75 van Ballegooijen AJ, Kestenbaum B, Sachs MC, de Boer IH, Siscovick DS, Hoof- and cardiovascular disease. Metabolism 2014; 63(1): 20–31. nagle AN et al. Association of 25-hydroxyvitamin D and parathyroid hormone 52 Brown JM, Vaidya A. Interactions between adrenal-regulatory and calcium- with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis). JAm regulatory hormones in human health. Curr Opin Endocrinol Diabetes Obes 2014; Coll Cardiol 2014; 63(12): 1214–1222. 21(3): 193–201. 76 van Ballegooijen AJ, Visser M, Kestenbaum B, Siscovick DS, de Boer IH, 53 Resnick LM, Laragh JH. Calcium metabolism and parathyroid function in primary Gottdiener JS et al. Relation of vitamin D and parathyroid hormone to cardiac aldosteronism. Am J Med 1985; 78(3): 385–390. biomarkers and to left ventricular mass (from the Cardiovascular Health Study). 54 Rossi E, Sani C, Perazzoli F, Casoli MC, Negro A, Dotti C. Alterations of calcium Am J Cardiol 2013; 111(3): 418–424. metabolism and of parathyroid function in primary aldosteronism, and their 77 Tomaschitz A, Pilz S. Interplay between sodium and calcium regulatory hor- reversal by spironolactone or by surgical removal of aldosterone-producing mones: a clinically relevant research field. Hypertension 2014; 63(2): 212–214. adenomas. Am J Hypertens 1995; 8(9): 884–893. 78 Isales CM, Barrett PQ, Brines M, Bollag W, Rasmussen H. Parathyroid hormone 55 Pilz S, Kienreich K, Drechsler C, Ritz E, Fahrleitner-Pammer A, Gaksch M et al. modulates angiotensin II-induced aldosterone secretion from the adrenal Hyperparathyroidism in patients with primary aldosteronism: cross-sectional and glomerulosa cell. Endocrinology 1991; 129(1): 489–495. interventional data from the GECOH study. J Clin Endocrinol Metab 2012; 97(1): 79 Mazzocchi G, Aragona F, Malendowicz LK, Nussdorfer GG. PTH and PTH-related E75–E79. peptide enhance steroid secretion from human adrenocortical cells. Am J Physiol 56 Maniero C, Fassina A, Seccia TM, Toniato A, Iacobone M, Plebani M et al. Endocrinol Metab 2001; 280(2): E209–E213. Mild hyperparathyroidism: a novel surgically correctable feature of primary 80 Hulter HN, Melby JC, Peterson JC, Cooke CR. Chronic continuous PTH infusion aldosteronism. J Hypertens 2012; 30(2): 390–395. results in hypertension in normal subjects. J Clin Hypertens 1986; 2(4): 360–370. 57 Rossi GP, Ragazzo F, Seccia TM, Maniero C, Barisa M, Calo LA et al. Hyperpar- 81 Saussine C, Judes C, Massfelder T, Musso MJ, Simeoni U, Hannedouche T et al. athyroidism can be useful in the identification of primary aldosteronism due to Stimulatory action of parathyroid hormone on renin secretion in vitro: a study aldosterone-producing adenoma. Hypertension 2012; 60(2): 431–436. using isolated rat kidney, isolated rabbit glomeruli and superfused dispersed rat 58 Chhokar VS, Sun Y, Bhattacharya SK, Ahokas RA, Myers LK, Xing Z et al. Loss of juxtaglomerular cells. Clin Sci 1993; 84(1): 11–19. bone minerals and strength in rats with aldosteronism. Am J Physiol Heart Circ 82 Helwig JJ, Musso MJ, Judes C, Nickols GA. Parathyroid hormone and calcium: Physiol 2004; 287(5): H2023–H2026. interactions in the control of renin secretion in the isolated, nonfiltering 59 Runyan AL, Chhokar VS, Sun Y, Bhattacharya SK, Runyan JW, Weber KT. Bone loss rat kidney. Endocrinology 1991; 129(3): 1233–1242. in rats with aldosteronism. Am J Med Sci 2005; 330(1): 1–7. 83 Fallo F, Rocco S, Pagotto U, Zangari M, Luisetto G, Mantero F. Aldosterone and 60 Salcuni AS, Palmieri S, Carnevale V, Morelli V, Battista C, Guarnieri V et al. Bone pressor responses to angiotensin II in primary hyperparathyroidism. J Hypertens involvement in aldosteronism. J Bone Miner Res 2012; 27(10): 2217–2222. Suppl 1989; 7(6): S192–S193.

Journal of Human Hypertension (2015) 515 – 521 © 2015 Macmillan Publishers Limited RAAS and calcium-regulatory hormones A Vaidya et al 521 84 Barkan A, Marilus R, Winkelsberg G, Yeshurun D, Blum I. Primary hyperpar- 99 Joergensen C, Tarnow L, Goetze JP, Rossing P. Vitamin D analogue therapy, athyroidism: possible cause of primary hyperaldosteronism in a 60-year- cardiovascular risk and kidney function in people with Type 1 diabetes mellitus old woman. J Clin Endocrinol Metab 1980; 51(1): 144–147. and diabetic nephropathy: a randomized trial. Diabetes Med (e-pub ahead of 85 Bernini G, Moretti A, Lonzi S, Bendinelli C, Miccoli P, Salvetti A. Renin–angio- print 11 October 2014; doi:10.1111/dme.12606). tensin–aldosterone system in primary hyperparathyroidism before and after 100 Scragg R, Slow S, Stewart AW, Jennings LC, Chambers ST, Priest PC et al. surgery. Metabolism 1999; 48(3): 298–300. Long-term high-dose vitamin D3 supplementation and blood pressure in 86 Tomaschitz A, Pilz S, Ritz E, Grammer T, Drechsler C, Boehm BO et al. Indepen- healthy adults: A Randomized Controlled Trial. Hypertension 2014; 64(4): dent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and 725–730. the renin-angiotensin system The Ludwigshafen Risk and Cardiovascular Health 101 Witham MD, Price RJ, Struthers AD, Donnan PT, Messow CM, Ford I et al. Cho- (LURIC) Study. Clin Chim Acta 2010; 411(17-18): 1354–1360. lecalciferol treatment to reduce blood pressure in older patients with isolated 87 Li YC. Vitamin D regulation of the renin–angiotensin system. J Cell Biochem 2003; systolic hypertension: the VitDISH randomized controlled trial. JAMA Intern Med 88(2): 327–331. 2013; 173(18): 1672–1679. 88 Li YC. Inhibition of renin: an updated review of the development of renin inhi- 102 Arora P, Song Y, Dusek J, Plotnikoff G, Sabatine M, Cheng S et al. Vitamin D bitors. Curr Opin Invest Drugs 2007; 8(9): 750–757. therapy in individuals with pre-hypertension or hypertension: The DAYLIGHT 89 Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a Trial. Circulation (e-pub ahead of print 30 October 2014). negative endocrine regulator of the renin–angiotensin system. J Clin Invest 2002; 103 Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D et al. The VITamin 110(2): 229–238. D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized 90 Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE et al. 1,25-dihydroxyvitamin controlled trial of vitamin D and marine omega-3 fatty acid supplements for the D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 33 – response element in the renin gene promoter. J Biol Chem 2007; 282(41): 2012; (1): 159 171. 29821–29830. 104 Powe CE, Karumanchi SA, Thadhani R. Vitamin D-binding protein and vitamin D 370 – 91 Zhang Y, Deb DK, Kong J, Ning G, Wang Y, Li G et al. Long-term therapeutic in blacks and whites. N Engl J Med 2014; (9): 880 881. effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong 105 Hollis BW, Bikle DD. Vitamin D-binding protein and vitamin D in blacks 370 – synergism with AT1 receptor antagonist. Am J Physiol Renal Physiol 2009; 297(3): and whites. N Engl J Med 2014; (9): 879 880. F791–F801. 106 Park HY, Kim JH, Bae S, Choi YY, Park JY, Hong YC. Interaction effect of serum 92 Zhang Y, Kong J, Deb DK, Chang A, Li YC. Vitamin D receptor attenuates renal 25-hydroxyvitamin D levels and CYP1A1, CYP1B1 polymorphisms on blood pressure in an elderly population. J Hypertens 2015; 33(1): 69–76. fibrosis by suppressing the renin–angiotensin system. J Am Soc Nephrol 2010; 21 107 Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D et al. (6): 966–973. Common genetic determinants of vitamin D insufficiency: a genome-wide 93 Freundlich M, Li YC, Quiroz Y, Bravo Y, Seeherunvong W, Faul C et al. Paricalcitol association study. Lancet 2010; 376(9736): 180–188. downregulates myocardial renin-angiotensin and fibroblast growth factor 108 Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and expression and attenuates cardiac hypertrophy in uremic rats. Am J Hypertens. biology of vitamin D receptor polymorphisms. Gene 2004; 338(2): 143–156. 2014; 27(5): 720–726. 109 McGrath JJ, Saha S, Burne TH, Eyles DW. A systematic review of the association 94 Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation between common single nucleotide polymorphisms and 25-hydroxyvitamin D of the renin–angiotensin system in humans. Hypertension 2010; 55(5): concentrations. J Steroid Biochem Mol Biol 2010; 121(1–2): 471–477. 1283–1288. 110 Wang L, Ma J, Manson JE, Buring JE, Gaziano JM, Sesso HD. A prospective study 95 Vaidya A, Forman JP, Seely EW, Williams JS. 25-Hydroxyvitamin D is Associated of plasma vitamin D metabolites, vitamin D receptor gene polymorphisms, and with plasma renin activity and the pressor response to dietary sodium intake in risk of hypertension in men. Eur J Nutr 2013; 52(7): 1771–1779. caucasians. J Renin-Angiotensin-Aldosterone Syst 2011; 12(3): 311–319. 111 Swapna N, Vamsi UM, Usha G, Padma T. Risk conferred by FokI polymorphism of 96 Carrara D, Bernini M, Bacca A, Rugani I, Duranti E, Virdis A et al. Cholecalciferol vitamin D receptor (VDR) gene for essential hypertension. Indian J Hum Genet administration blunts the systemic renin–angiotensin system in essential 2011; 17(3): 201–206. hypertensives with hypovitaminosis D. J Renin-Angiotensin-Aldosterone Syst 2014; 112 Solak Y, Covic A, Kanbay M. What do we know and do not know about vitamin 15 – (1): 82 87. D?: A causal association between vitamin D receptor genetic polymorphism and 97 Larsen T, Mose FH, Bech JN, Pedersen EB. Effect of paricalcitol on renin and hypertension. J Clin Hypertens (Greenwich) 2014; 16(9): 627–628. – albuminuria in non-diabetic stage III IV chronic kidney disease: a randomized 113 Vaidya A, Sun B, Forman JP, Hopkins PN, Brown NJ, Kolatkar NS et al. The vitamin 14 placebo-controlled trial. BMC Nephrol 2013; : 163. D receptor gene polymorphism Fok1 is associated with plasma renin activity in 98 de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T et al. caucasians. Clin Endocrinol (Oxf) 2011; 74(6): 783–790. Selective vitamin D receptor activation with paricalcitol for reduction of 114 Levin GP, Robinson-Cohen C, de Boer IH, Houston DK, Lohman K, Liu Y et al. albuminuria in patients with type 2 diabetes (VITAL study): a randomised Genetic variants and associations of 25-hydroxyvitamin D concentrations with 376 – controlled trial. Lancet 2010; (9752): 1543 1551. major clinical outcomes. JAMA 2012; 308(18): 1898–1905.