Human Interventions to Characterize Novel Relationships Between the Renin–Angiotensin–Aldosterone System and Parathyroid Hormone
Abstract
Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin–angiotensin–aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (−12%) and PTH (−9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.
Introduction
Characterization of the complex endocrine relationships between sodium- and calcium-regulatory hormones is evolving. Calcium,1,2 vitamin D,3–9 and parathyroid hormone (PTH)10–12 have been implicated in regulating the renin–angiotensin–aldosterone system (RAAS), and the RAAS, in turn, has been implicated in regulating these calcium- regulatory hormones.13–16 In particular, recent observational studies in individuals with primary hyperaldosteronism (PA) suggest that excess aldosterone may result in hyperparathyroidism.15–17 A better understanding of the normal physiological relationship between the RAAS and PTH is of clinical relevance because inappropriate activity of both PTH and the RAAS may negatively impact cardiovascular18–26 and skeletal health.27,28
Human evidence characterizing the positive relationship between RAAS activity and PTH has largely originated from observational studies in disease states such as hyperaldosteronism15,16 and chronic kidney disease (CKD).29 Spironolactone therapy is associated with lower fracture risk in heart failure27; patients with PA have reduced bone mineral density and a higher rate of osteoporosis30; and PA is associated with elevated PTH levels that are lowered after clinically indicated surgical or medical therapy for PA.14–16 Furthermore, the use of RAAS inhibitors is associated with lower PTH levels in CKD.29
The aforementioned studies provided noteworthy evidence to advance the understanding of RAAS–PTH interactions; however, they were observational in nature and were performed in populations with severe disease (heart failure, PA, and CKD) where abnormalities in calcium, renal function, and volume homeostasis can be confounding. We hypothesized that physiological interactions between the RAAS and PTH exist, and that characterization of these physiological relationships may improve the understanding of the pathophysiology and treatment of disease states such as PA and hyperparathyroidism (HPTH). To this end, we evaluated the impact of modulating individual RAAS components on PTH from 4 previously performed human intervention studies.
Methods
General Overview of Study Protocols
We performed post hoc analyses of controlled RAAS and calcium-regulatory hormone interventions from 4 human interventional study protocols in individuals without PA, HPTH, CKD, or heart disease. The subjects in all 4 studies were overweight or obese, as previously reported,4 but had comparable 25-hydroxyvitamin D concentrations (Table 1). All study protocols were performed in a clinical research center under conditions of controlled posture, diet, and time of day, and after withdrawal of medications known to modulate the RAAS. Studies 1 and 2 examined the relationship between acute, generalized RAAS modulation and PTH. In study 1, we performed secondary analyses to evaluate the acute PTH-responses to an infusion of angiotensin II (Ang II) and to an angiotensin-converting enzyme (ACE) inhibitor (captopril), interventions expected to acutely stimulate and inhibit both circulating Ang II and aldosterone, respectively. Furthermore, these PTH-responses were evaluated in subjects with vitamin D deficiency and again after treatment with high-dose vitamin D3 therapy because modulation of vitamin D status modulates PTH and has been shown to modulate the tissue-responsiveness to Ang II in humans.4,6,31 In study 2, we evaluated the dose-dependent relationship between PTH and the RAAS in a similar population to study 1. Studies 3 and 4 focused specifically on the relationship between aldosterone and PTH. In study 3, we evaluated the acute effect of aldosterone on PTH in subjects who were randomized to receive an infusion of aldosterone or vehicle in a blinded manner and then crossed over to receive the alternate infusion. Study 4 examined the impact of 6 weeks of double-blinded randomization to either spironolactone or placebo on PTH. Finally, we performed in vitro studies to assess the expression of Ang II type I receptor (AT1R) and mineralocorticoid receptor (MR) in normal and adenomatous human parathyroid tissue. All subjects provided informed consent, and all study procedures described below were approved by the Institutional Review Boards of Brigham and Women’s Hospital (Boston, MA; studies 1, 2, 4, and in vitro studies) and Vanderbilt University Medical Center (Nashville, TN; study 3).
Characteristics | Study 1 | Study 2 | Study 3 | Study 4 |
---|---|---|---|---|
n | 14 | 14 | 10 | 27 |
Age, y | 50±2 | 49±3 | 47±3 | 43±2 |
% Female | 64 | 21 | 70 | 63 |
% Black | 70 | 36 | 30 | 41 |
BMI, kg/m2 | 36.0±1 | 29.5±1 | 33.4±1 | 37.1±1 |
25(OH)D, ng/mL | 16.6±1.9 | 22.6±2.7 | 19.2±2.2 | 21.3±1.5 |
Data are presented as means±SEM, where applicable. All non-black subjects were white with the exception of 1 Asian-American subject in study 2. 25(OH)D indicates 25-hydroxyvitamin D; and BMI, body mass index.
Study 1: Population and Study Protocol
The study 1 population and protocol have been previously described4 although the data and analyses presented here are novel. The complete study population and protocol details are available in the online-only Data Supplement.
Study 2: Population and Study Protocol
Subjects from study 2 have never been previously reported. Study 2 is an ongoing interventional physiology study recruiting participants to establish genotype/phenotype correlations in hypertension (NCT01426529). The inclusion criteria and study protocol for study 2 can be seen in the online-only Data Supplement.
Study 3: Population and Study Protocol
Study 3 recruited nondiabetic participants aged 18 to 70 years with the metabolic syndrome to assess the effects of aldosterone on glucose metabolism. In total, 10 subjects who completed the study protocol and had available frozen samples for secondary analysis of PTH were included (NCT00732160).
Study 3 participants were maintained on a liberal sodium diet that included >160 mmol/d of sodium, 100 mmol/d of potassium, 1000 mg of calcium, and calories calculated for weight maintenance. Antihypertensive medications were withdrawn for a minimum of 3 weeks before study procedures. Subjects reported for admission to the Vanderbilt clinical research center in the evening and were randomized to an infusion of aldosterone (0.7 µg/kg per hour in 5% dextrose water; Professional Compounding Corporation of America) or vehicle for 12.5 hours starting at 10 pm. The next day, subjects received infusion of the other study drug (aldosterone/vehicle) in the same fashion. Samples were drawn before infusion and at 10 hours during each infusion for PTH analysis. To mitigate the potassium-wasting effect of aldosterone infusion, potassium chloride was administered as needed to maintain serum potassium ≥3.7 mmol/L during each infusion.
Study 4: Population and Study Protocol
Study 4 recruited obese, normotensive participants aged 18 to 70 years to evaluate the effect of MR antagonist therapy versus placebo on vascular function in a randomized and double-blinded design (NCT01406015). In total, 32 subjects completed the study, of which 27 had available blood and urine to perform additional analyses. These 27 subjects were selected for our analyses before unblinding of their intervention status or knowledge of their intervention outcomes.
Subjects in study 4 completed the same diets and washout procedures as described above for studies 1 and 2 before clinical research center admission. On the morning of their first study visit, subjects had blood sampling that was used in this secondary analysis to measure PTH and other relevant calcium-regulatory components. Subjects also underwent other procedures during this study visit after blood sampling (including vascular hemodynamic protocols) that are not described herein because they are not relevant to the current study aims. All subjects were discharged home with a double-blinded randomized study drug that was 1 tablet daily of either spironolactone 50 mg or placebo. After 6 weeks of therapy, subjects returned on the study diet for a second overnight visit to the clinical research center, and study procedures were repeated the next morning.
Laboratory Assays
Full details of the timing and methods of laboratory assays are provided in the online-only Data Supplement.
In Vitro Studies to Assess RAAS Receptors in Human Parathyroid Tissue
To evaluate the roles of Ang II and aldosterone in parathyroid regulation, we obtained normal and adenomatous parathyroid tissue from a patient with primary hyperparathyroidism who underwent a routine neck exploration for parathyroidectomy with hemithyroidectomy. Histopathology confirmed the procurement of a single parathyroid adenoma and a single normal parathyroid gland adherent to thyroid tissue. The full methodological details describing protein and mRNA analysis are in the online-only Data Supplement.
Statistical Analyses
Here, we describe post hoc analyses of the aforementioned 4 interventional study protocols with the objective of evaluating the influence of specific RAAS modulations on PTH in relatively healthy populations without PA, CKD, heart disease, or HPTH. All variables presented were normally distributed and were not transformed in any way. All values are presented as means±SEM. A 2-tailed P<0.05 was considered statistically significant.
In all studies, paired t tests were used when comparing intraindividual changes in normally distributed variables. Because basal PTH values were altered by the vitamin D3 intervention in study 1 (an expected physiological change), we present PTH values not only as absolute values but also as the percentage change from baseline to allow a proportional comparison of PTH-responses. In study 3, in which subjects were randomized and crossed over to both interventions (aldosterone and vehicle infusion), we also compare the intraindividual change in each variable attributable to intervention using paired t tests. In study 4, the impact of the intervention (spironolactone or placebo) on each independent population was compared using an ANOVA model, in which the postintervention PTH was the outcome, and adjustment for the preintervention PTH value was included. Analyses were performed using SAS 9.2 (SAS Institute, Cary, NC).
Results
Study 1: PTH-Responses to Acute RAAS Modulations and the Influence of Vitamin D Status
Infusion of Ang II (1 ng/kg per minute) in a vitamin D–deficient state resulted in an expected rise in serum aldosterone (+148%; as previously described)4 but also a +10.3% increase in PTH from baseline (Figure A). A single dose of captopril lowered serum aldosterone levels (−12%) and also acutely lowered PTH below basal levels (−9.7%), and thereafter a second infusion of Ang II after captopril administration resulted in an enhanced stimulation of PTH (+16.0% from baseline; Figure A). When these study procedures were repeated after high-dose vitamin D3 therapy to induce a vitamin D–sufficient state, significant changes in PTH-responses to RAAS provocations were observed: the PTH-response to an initial Ang II infusion was more robust (+26.4% from baseline; Figure B); captopril induced a smaller nonsignificant acute reduction in PTH (−6.8%) and had a negligible effect on the magnitude of subsequent Ang II-mediated PTH stimulation (Figure B). These results parallel our previous observations in these same study subjects, where vitamin D3 therapy augmented the tissue (vascular and adrenal) response to Ang II infusion and marginalized the influence of an ACE inhibitor.4

Study 2: PTH-Responses to Higher Dose Ang II Infusion
Study 2 investigated the impact of a higher dose Ang II infusion on PTH. In comparison with study 1, the infusion of 3 ng/kg per minute of Ang II resulted in greater increment in aldosterone (+241%) and a more robust PTH-response (+36% from baseline), which were independent of any acute changes in serum calcium or 1,25-dihydroxyvitamin D concentrations (Figure C). When integrated with the findings from study 1 (Figure A–C), an incremental relationship between the RAAS and PTH was observed, which was modulated by Ang II dose, as well as by ACE inhibition and vitamin D status (both of which sensitize the tissue responsiveness to Ang II infusion).4,6,31–33
Study 3: PTH-Responses to Aldosterone Infusion
To isolate whether the aforementioned acute modulations in PTH induced by Ang II infusion were mediated by Ang II itself or aldosterone, study 3 investigated the impact of an aldosterone infusion on PTH. Baseline PTH levels before aldosterone and vehicle infusions were similar (Table S1 in the online-only Data Supplement). The infusion of aldosterone resulted in a robust increase in serum aldosterone concentration (+892%) that was substantially higher than that induced by Ang II infusions in studies 1 and 2, as well as nonsignificant trends of increased blood pressure and decreased potassium. However, PTH was not modified by the infusion of aldosterone when compared with vehicle (Table S1).
Study 4: PTH-Responses to Chronic MR Antagonist Therapy
Although an aldosterone infusion did not influence PTH in the acute setting, we evaluated the effect of chronic aldosterone blockade on PTH in study 4 because the findings of Rossi et al and Tomaschitz et al have suggested that chronic aldosterone excess in PA may increase PTH.15,16 The effect of chronic spironolactone therapy was evident within the treatment group via increments in aldosterone concentrations and decrements in blood pressure (Tables 2 and 3). When comparing the preintervention versus postintervention effect of each treatment arm, neither placebo nor spironolactone therapy significantly altered the levels of PTH, serum calcium, 25-hydroxyvitamin D, or markers of bone formation and resorption during 6 weeks (Tables 2 and 3). However, analyses comparing the change in these parameters induced by each intervention revealed a decrease in serum calcium and increase in PTH in the placebo group (possibly mediated by chronic and persistent vitamin D deficiency) that was significantly blunted by spironolactone treatment (Tables 2 and 3, ANOVA P value). A similar nonsignificant trend was seen with respect to C-telopeptide levels.
Demographic and Biochemical Results | Placebo | Spironolactone | P Value |
---|---|---|---|
Age, y | 40.8±3 | 45.4±3 | 0.32 |
% Female | 69 | 57 | 0.54 |
% Black | 54 | 29 | 0.82 |
BMI, kg/m2 | 36.1±1 | 38.1±2 | 0.42 |
Subjects were randomized to either spironolactone (50 mg/d) or placebo for 6 wk with blood measurements before and after the intervention period. In addition, the difference in the change in each variable induced by the interventions is presented in the far right column. BMI indicates body mass index.
Clinical and Biochemical Parameters | Placebo | Spironolactone | ANOVA P Value | ||||
---|---|---|---|---|---|---|---|
Pre | Post | Pre vs Post P Value | Pre | Post | Pre vs Post P Value | ||
Systolic blood pressure, mm Hg | 119±4 | 120±3 | 0.70 | 123±3 | 117±3 | 0.0004 | <0.05 |
Diastolic blood pressure, mm Hg | 71±2 | 72±2 | 0.54 | 72±2 | 70±2 | 0.19 | 0.21 |
Serum potassium, mmol/L | 4.2±0.1 | 4.1±0.1 | 0.51 | 4.1±0.1 | 4.2±0.1 | 0.28 | 0.47 |
Aldosterone, ng/dL | 3.6±0.4 | 3.1±0.3 | 0.30 | 3.3±0.4 | 6.6±1.4 | 0.04 | <0.05 |
Urine aldosterone excretion rate, µg/24 h | 11.1±1.7 | 9.2±1.9 | 0.38 | 7.5±1.2 | 12.2±2.0 | 0.06 | 0.18 |
Serum calcium, mg/dL | 9.0±0.1 | 8.8±0.1 | 0.10 | 8.9±0.1 | 9.0±0.1 | 0.49 | <0.05 |
25(OH)D, ng/mL | 18.4±2.0 | 19.8±2.3 | 0.32 | 24.0±1.9 | 24.0±2.1 | 0.93 | 0.484 |
PTH, pg/mL | 41±4 | 45±4 | 0.07 | 38±3 | 37±3 | 0.31 | <0.05 |
C-terminal telopeptide, ng/mL | 0.46±0.1 | 0.50±0.1 | 0.09 | 0.51±0.1 | 0.48±0.1 | 0.28 | 0.07 |
Procollagen type 1 N-terminal propeptide, µg/L | 39±4 | 41±4 | 0.60 | 44±5 | 43±5 | 0.58 | 0.57 |
Subjects were randomized to either spironolactone (50 mg/d) or placebo for 6 wk with blood measurements before and after the intervention period. The preintervention and postintervention values for each variable are presented with a probability value reflecting the paired comparison. In addition, the difference in the change in each variable induced by the interventions is presented in the far right column. 25(OH)D indicates 25-hydroxyvitamin D; and PTH, parathyroid hormone.
In Vitro Studies to Assess RAAS-Related Receptors in Human Parathyroid Tissue
AT1R and MR protein levels were detected in normal human parathyroid tissue (Figure S1); normal parathyroid tissue had relatively similar AT1R and MR protein levels when compared with mouse adrenal tissue. In addition, AT1R and MR protein levels were detected in parathyroid adenoma tissue of the same patient, with a 2- to 4-fold increase in expression when compared with normal parathyroid and mouse adrenal tissues. To further confirm AT1R and MR expression in parathyroid tissue, we quantified mRNA levels and observed expression in normal parathyroid tissue and a 3- to 4-fold increase in expression within adenomatous tissue (Figure S1).
Discussion
Our data demonstrate novel physiological relationships between PTH and RAAS activity in humans without PA for the first time. Despite the notable limitations of our methods (the use of 4 small and separate study populations of obese individuals, post hoc analyses, and the absence of data on ionized and urinary calcium that could help uncover underlying mechanisms), we have nonetheless demonstrated new pleiotropic relationships between RAAS components and PTH that may have important implications for the treatment of PTH-mediated disorders.
Relationships between the RAAS and calcium-regulatory hormones that were initially identified in the past13,14,34,35 have recently been revisited and complemented by data that shed new insights into the complex interactions between these hormone systems: vitamin D3–6,11 and calcium1,2 seem to regulate renin, and a reciprocal relationship between the RAAS and PTH has been proposed.15,16,36,37 The latter has largely stemmed from observational studies in PA that implicate aldosterone as a regulator of PTH. Inappropriately elevated serum aldosterone has been associated with high PTH levels that are lowered with treatment of PA.14–16 Together these studies describe a pathophysiology in states of chronic aldosterone excess whereby hyperparathyroidism is induced, possibly secondary to aldosterone-mediated hypercalciuria.14–16 Herein, we extend the findings of these previous studies with analyses from controlled human interventional protocols to evaluate the physiological relationship between the RAAS and PTH in the absence of PA. Our findings, in the context of previous work by Tomaschitz et al36 and Rossi et al,37 raise important questions that warrant discussion for future studies. Is PTH regulated by Ang II, aldosterone, or both? Does the physiological relationship between PTH and the RAAS differ with respect to the duration of RAAS modulations (acute versus chronic), or in physiological versus pathophysiologic states? What significance do these findings have for cardiovascular and skeletal health?
Is PTH Regulated by Ang II?
Identifying whether PTH is regulated by Ang II, or aldosterone, or both, could have implications for pharmacological therapies. Our results demonstrate that raising circulating Ang II and aldosterone acutely stimulates PTH in a dose-dependent manner, whereas lowering endogenous Ang II and aldosterone acutely with an ACE inhibitor lowers PTH (Table S2: columns a+b). Because elevated aldosterone levels have been associated with elevated PTH levels in PA,14,16,17 we hypothesized that an acute aldosterone infusion would also raise PTH. However, despite an acute 10-fold increase in serum aldosterone concentrations in study 3, PTH remained unchanged (Table S2: column d), implicating Ang II as the primary stimulus for PTH in the acute setting. The role of Ang II as the mediator of these effects was further supported by the fact that the regulation of PTH was influenced by interventions known to sensitize tissue-responsiveness to Ang II4,33: both ACE inhibition and vitamin D3 therapy independently enhanced the PTH-response to Ang II infusion. We previously showed that vitamin D deficiency blunts tissue-responsiveness to exogenous Ang II by inducing a state of high tissue-RAAS activity4,6,31; this blunted sensitivity to Ang II could be corrected by lowering the tissue-RAAS with an ACE inhibitor or vitamin D3 therapy.4,33 Consistent with this phenomenon, in study 1, we observed an increase in PTH with Ang II infusion that was augmented after captopril in the vitamin D–deficient state. The PTH-response to Ang II was further enhanced in the same subjects after vitamin D3 therapy, which also marginalized the influence of captopril on subsequent Ang II infusions (presumptively attributable to maximal suppression of the endogenous tissue-RAAS with vitamin D3 therapy).4 Our identification of AT1R in normal and adenomatous human parathyroid tissue is a novel finding that further supports an acute and direct effect of Ang II on PTH; we speculate that given the acuity of the findings, Ang II may regulate the secretion of preformed PTH. Whether the effect of Ang II on PTH persists beyond the acute period remains unknown (Table S2: column c); however, the finding that a parathyroid adenoma expresses higher levels of AT1R than normal parathyroid may implicate Ang II in the pathogenesis and progression of hyperparathyroidism. An ongoing interventional study, The RAAS-PARC (Renin-Angiotensin-Aldosterone System and Parathyroid Hormone Control) study (NCT01691781), will provide insight into PTH-responses to acute and chronic ACE inhibition in individuals with primary hyperparathyroidism in comparison with normal healthy controls.
Is PTH Regulated by Aldosterone?
Alternatively, our findings suggest that in the chronic setting, it may be aldosterone rather than Ang II which directly and indirectly stimulates PTH. This mechanism has been proposed13–17 in observational reports in patients with PA (a condition where aldosterone levels are chronically elevated with concomitant suppression of Ang II and renin). Some of these observational reports included abnormalities in renal function and changes in serum and urinary calcium, which may have also contributed to PTH effects.14–16 In addition, chronic MR antagonism has even been observationally associated with reduced fracture risk,27 implicating PTH regulation by aldosterone as a potential mediator of this outcome. In our study 4, chronic MR antagonism may have modestly lowered PTH and raised serum calcium. Although no change in PTH was observed in the group randomized to spironolactone treatment, PTH was significantly impacted by the spironolactone intervention when compared with the placebo-treated control (Table S2: column e). This phenomenon may have reflected a mild progressive secondary hyperparathyroidism in the placebo group attributable to chronic vitamin D deficiency that was blunted by spironolactone. Interestingly, this observation was seen despite the fact that MR antagonism should raise Ang II concentrations and in a population with low aldosterone levels (subjects did not have PA and were on a liberal sodium diet); it is possible that the effect of spironolactone would have been more evident in a population with higher serum aldosterone,16 hyperparathyroidism, longer duration of treatment, or larger sample size. Although we did not have urine calcium measurements in this study, previous research has shown that chronic aldosterone excess results in hypercalciuria and hypocalcemia.16,38,39 Because we, along with Maniero et al,10 have identified the presence of MR in normal and abnormal parathyroid tissue, we speculate that aldosterone action through the MR may impact PTH during the long term by influencing PTH synthesis directly at the parathyroid gland and indirectly via renal regulation of calcium handling. The influence of MR antagonists on PTH may thus be most evident in populations with PA or HPTH, rather than relatively healthy individuals such as those in our studies. Studies of biochemical and clinical outcomes of MR antagonism in larger targeted populations will clarify this effect. The EPATH (Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism) Study (ISRCTN33941607)40 is designed to conclusively evaluate the influence of long-term MR antagonism on clinical outcomes in a large study population with primary hyperparathyroidism.
Is PTH Regulated by Both Ang II and Aldosterone?
Overall, our findings suggest pleiotropic effects of RAAS components on PTH that may vary with time of exposure. Although we used PTH levels as our outcome, it is important to realize that in endocrine systems, where feedback mechanisms are complex, the absolute circulating level of any hormone may not be sufficient to evaluate biological and clinical outcomes; the setting of a new homeostatic equilibrium may not be detected by circulating levels alone. Such a phenomenon, whereby levels of 1 hormone are maintained at the expense of changes to others, is common. For example, although ACE inhibitors acutely lower Ang II and aldosterone concentrations, chronic ACE inhibition results in a re-equilibration and normalization of aldosterone levels,41 yet the clinical benefits associated with chronic ACE inhibition remain highly favorable.42 The re-establishment of the PTH–RAAS equilibrium may be most evident in physiological states where both calcium- and sodium-regulatory hormones can modulate their activity appropriately. In contrast, in pathophysiologic states, such as PA or HPTH, normal mechanisms may be overwhelmed by the effects of excess aldosterone or PTH.
Strengths and Limitations
Our study has notable strengths and limitations. We describe post hoc analyses of previously performed studies, which were not principally designed for evaluation of RAAS–PTH relationships. However, although these analyses were secondary in nature, we used data from 4 human intervention studies that used careful methods to control modulators of the RAAS (including dietary electrolytes, posture, and antihypertensive medications) and calcium-regulatory hormones (including dietary calcium and vitamin D status). The sample sizes were small but were more than sufficient to detect robust changes in PTH (studies 1 and 2) and expected changes in serum aldosterone levels and blood pressure attributable to aldosterone infusion (study 3) and spironolactone (study 4). It is possible that a larger population in study 4 would have permitted greater power in detecting MR antagonist-induced changes in PTH and serum calcium; however, we suspect these would still have been modest in magnitude because the study population did not have PA or HPTH. Although the studies were performed in separate populations, as necessitated by the complex protocols performed in clinical research centers, these populations were similar across demographic variables and, although obese, were otherwise largely healthy. Obesity has been linked to a shift in the 25-hydroxyvitamin D-PTH relationship43; however, acute changes in PTH were observed using within-individual comparisons. We present possible explanations to account for a direct mechanism behind the RAAS-mediated effects we observed; however, calcium modulation has been implicated as a potential indirect mediator of RAAS–PTH interactions,12 and we did not have detailed electrolyte assessment, including magnesium and ionized and urinary calcium in all of our protocols. Of note, previous studies failed to show any modulation in ionized calcium with the Ang II infusion doses we used,35 thereby supporting a possible direct Ang II–mediated effect on PTH, as we propose. Finally, further studies will be needed to evaluate the role of additional factors in the modulation of the RAAS and PTH, including Klotho,44,45 changes in dietary electrolytes,36,46–48 and the use of more physiological doses of Ang II (because we used doses necessary to elicit observable effects).49
Perspectives
In summary, we describe novel and pleiotropic relationships between PTH and the RAAS in individuals without PA. Ang II seems to be an acute modulator of PTH, potentially through direct stimulation of PTH release via the AT1R at the parathyroid gland. In contrast, aldosterone may be involved in the modulation of PTH in the chronic setting via indirect and direct mechanisms. Our findings build on observations in pathophysiologic states10,13,16 by providing new insights into the complex relationships between calcium- and sodium-regulatory hormones that may exist in normal physiology. Ongoing40 and future interventional studies are likely to improve our understanding of these interactions and how they may influence the cardiovascular and skeletal outcomes associated with PTH-mediated disorders.
Novelty and Significance
•
We used interventional human studies to characterize novel physiological and pleiotropic relationships between the renin–angiotensin–aldosterone system and parathyroid hormone (PTH) and performed in vitro studies to support our clinical findings.
•
Understanding how components of the renin–angiotensin–aldosterone system modulate PTH may improve the understanding and treatment of PTH-mediated disorders.
Relationships between PTH and the renin–angiotensin–aldosterone system are pleiotropic. Angiotensin II acutely stimulates PTH release, possibly via direct action at the parathyroid gland, whereas aldosterone may be involved in the chronic stimulation of PTH via direct and indirect interactions.
Supplemental Material
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Accepted: 21 June 2013
Revision received: 7 July 2013
Received: 8 October 2013
Published online: 4 November 2013
Published in print: February 2014
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Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers: K23 HL111771-01 (A. Vaidya), K23 HL08236-05 (J.S. Williams), R01 HL104032 (L.H. Pojoga), K24 HL103845 (G.K. Adler), 5T32 HL007609-24 (A.E. Garza), K23 DK081662 (J.M. Luther). Research was also supported by a Brigham and Women’s Hospital Biomedical Research Institute Grant (A. Vaidya), a Harvard Medical School Research Fellowship (J.M. Brown), and the American Cancer Society under award MRSG-13-062-01 (D.T. Ruan). This project was supported by Clinical Translational Science Awards (UL1RR025758, UL1 RR024975) and grant M01-RR02635 to Harvard University, Brigham and Women’s Hospital, and Vanderbilt University from the National Center for Research Resources, and by the Specialized Center of Research in Molecular Genetics of Hypertension Grant P50HL055000. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
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