Journal of Human Hypertension (2015) 29, 515–521 © 2015 Macmillan Publishers Limited All rights reserved 0950-9240/15 www.nature.com/jhh 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,