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Publication Record


Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone.
Reddish MJ, Guengerich FP
(2019) J Biol Chem 294: 12975-12991
MeSH Terms: 18-Hydroxycorticosterone, Aldosterone, Biocatalysis, Cytochrome P-450 CYP11B2, Humans, Kinetics, Models, Molecular, Molecular Conformation
Show Abstract · Added March 3, 2020
Human cytochrome P450 (P450) 11B2 catalyzes the formation of aldosterone, the major endogenous human mineralocorticoid. Aldosterone is important for the regulation of electrolyte homeostasis. Mutations and overexpression of P450 11B2 (also known as aldosterone synthase) can lead to hypertension, congestive heart failure, and diabetic nephropathy. The enzyme is therefore a target for drug development to manage these various disorders. P450 11B2 catalyzes aldosterone formation from 11-deoxycorticosterone through three distinct oxidation steps. It is currently unknown to which degree these reactions happen in sequence without the intermediate products dissociating from the enzyme ( processively) or whether these reactions happen solely distributively, in which the intermediate products must first dissociate and then rebind to the enzyme before subsequent oxidation. We present here a comprehensive investigation of processivity in P450 11B2-catalyzed reactions using steady-state, pre-steady-state, pulse-chase, equilibrium-binding titrations, and stopped-flow binding studies. We utilized the data obtained to develop a kinetic model for P450 11B2 and tested this model by enzyme kinetics simulations. We found that although aldosterone is produced processively, the enzyme preferentially utilizes a distributive mechanism that ends with the production of 18-OH corticosterone. This seemingly contradictory observation could be resolved by considering the ability of the intermediate product 18-OH corticosterone to exist as a lactol form, with the equilibrium favoring the ring-closed lactol configuration. In summary, our refined model for P450 11B2 catalysis indicates isomerization of the intermediate to a lactol can explain why P450 11B2 must produce aldosterone through a processive mechanism despite favoring a distributive mechanism.
© 2019 Reddish and Guengerich.
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8 MeSH Terms
Mechanism of Hyperkalemia-Induced Metabolic Acidosis.
Harris AN, Grimm PR, Lee HW, Delpire E, Fang L, Verlander JW, Welling PA, Weiner ID
(2018) J Am Soc Nephrol 29: 1411-1425
MeSH Terms: Acidosis, Aldosterone, Amiloride, Ammonia, Animals, Cation Transport Proteins, Diuretics, Glutaminase, Hydrochlorothiazide, Hydrogen-Ion Concentration, Hyperkalemia, Kidney Tubules, Distal, Kidney Tubules, Proximal, Membrane Glycoproteins, Mice, Mice, Knockout, Protein-Serine-Threonine Kinases, Proton-Translocating ATPases, Urinalysis
Show Abstract · Added April 3, 2018
Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.
Copyright © 2018 by the American Society of Nephrology.
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19 MeSH Terms
RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice.
Taguchi K, Yamagishi SI, Yokoro M, Ito S, Kodama G, Kaida Y, Nakayama Y, Ando R, Yamada-Obara N, Asanuma K, Matsui T, Higashimoto Y, Brooks CR, Ueda S, Okuda S, Fukami K
(2018) Sci Rep 8: 2686
MeSH Terms: Acetates, Acute Kidney Injury, Aldosterone, Animals, Aptamers, Peptide, Blood Pressure, Desoxycorticosterone Acetate, Glycation End Products, Advanced, Hypertension, Kidney Diseases, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor for Advanced Glycation End Products, Receptors, Mineralocorticoid, Sodium Chloride, Dietary
Show Abstract · Added March 14, 2019
The mineralocorticoid receptor (MR) and its downstream signaling play an important role in hypertensive renal injury. The interaction of advanced glycation end products (AGE) with their receptor (RAGE) is involved in the progression of renal disease. However, the pathological crosstalk between AGE-RAGE axis and MR system in kidney derangement remains unclear. We screened DNA-aptamer directed against RAGE (RAGE-apt) in vitro and examined its effects on renal injury in uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice. RAGE, GTP-bound Rac-1 (Rac1), and MR were co-localized in the podocytes of DOCA mice. The deletion of RAGE gene significantly inhibited mesangial matrix expansion and tubulointerstitial fibrosis in DOCA mice, which was associated with the reduction of glomerular oxidative stress, MR, Rac1, and urinary albumin excretion (UAE) levels. RAGE-apt attenuated the increase in carboxymethyllysine (CML), RAGE, nitrotyrosine, Rac1, and MR levels in the kidneys and reduced UAE in DOCA mice. Aldosterone (Aldo) increased nitrotyrosine, CML, and RAGE gene expression in murine podocytes, whereas CML stimulated MR and Rac1 levels, which were blocked by RAGE-apt. The present study indicates the crosstalk between the AGE-RAGE axis and Aldo-MR system, suggesting that RAGE-apt may be a novel therapeutic tool for the treatment of MR-associated renal diseases.
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18 MeSH Terms
The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study.
Brown JM, Robinson-Cohen C, Luque-Fernandez MA, Allison MA, Baudrand R, Ix JH, Kestenbaum B, de Boer IH, Vaidya A
(2017) Ann Intern Med 167: 630-641
MeSH Terms: Aged, Aged, 80 and over, Aldosterone, Cross-Sectional Studies, Female, Humans, Hyperaldosteronism, Hypertension, Incidence, Longitudinal Studies, Male, Middle Aged, Potassium, Receptors, Mineralocorticoid, Renin, Risk Factors
Show Abstract · Added October 24, 2017
Background - Primary aldosteronism is recognized as a severe form of renin-independent aldosteronism that results in excessive mineralocorticoid receptor (MR) activation.
Objective - To investigate whether a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons.
Design - Cohort study.
Setting - National community-based study.
Participants - 850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA).
Measurements - Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and MR activity, assessed via serum potassium and urinary fractional excretion of potassium.
Results - A suppressed renin phenotype was associated with a higher rate of incident hypertension than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed.
Limitation - Sodium and potassium were measured several years before renin and aldosterone.
Conclusion - Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension.
Primary Funding Source - National Institutes of Health.
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16 MeSH Terms
Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules.
Grimm PR, Coleman R, Delpire E, Welling PA
(2017) J Am Soc Nephrol 28: 2597-2606
MeSH Terms: Aldosterone, Animals, Blood Pressure, Epithelial Sodium Channels, Hydrochlorothiazide, Kidney Tubules, Distal, Mice, Natriuresis, Phosphorylation, Potassium, Potassium Channels, Inwardly Rectifying, Protein-Serine-Threonine Kinases, Pseudohypoaldosteronism, Signal Transduction, Sodium Chloride Symporter Inhibitors, Solute Carrier Family 12, Member 3
Show Abstract · Added May 3, 2017
Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mouse gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK). Renal expression of the constitutively active (CA)-SPAK mutant was specifically targeted to the early DCT using a DCT-driven Cre recombinase. CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia, concurrent with NCC hyperphosphorylation. However, thiazide-mediated inhibition of NCC and consequent restoration of sodium excretion did not immediately restore urinary potassium excretion in CA-SPAK mice. Notably, CA-SPAK mice exhibited ASDN remodeling, involving a reduction in connecting tubule mass and attenuation of epithelial sodium channel (ENaC) and ROMK expression and apical localization. Blocking hyperactive NCC in the DCT gradually restored ASDN structure and ENaC and ROMK expression, concurrent with the restoration of urinary potassium excretion. These findings verify that NCC hyperactivity underlies FHHt but also reveal that NCC-dependent changes in the driving force for potassium secretion are not sufficient to explain hyperkalemia. Instead, a DCT-ASDN coupling process controls potassium balance in health and becomes aberrantly activated in FHHt.
Copyright © 2017 by the American Society of Nephrology.
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1 Members
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16 MeSH Terms
B-Type Natriuretic Peptide, Aldosterone, and Fluid Management in ARDS.
Semler MW, Marney AM, Rice TW, Nian H, Yu C, Wheeler AP, Brown NJ, NIH NHLBI ARDS Network
(2016) Chest 150: 102-11
MeSH Terms: Adult, Aged, Aldosterone, Biomarkers, Female, Fluid Therapy, Hospital Mortality, Humans, Male, Middle Aged, Natriuretic Peptide, Brain, Outcome Assessment, Health Care, Respiratory Distress Syndrome, Statistics as Topic, Water-Electrolyte Balance
Show Abstract · Added April 6, 2017
BACKGROUND - Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival.
METHODS - This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality.
RESULTS - Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P < .001) and decreased mortality (19% vs 30%, P = .03) (P value for interaction = .01).
CONCLUSIONS - In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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1 Members
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15 MeSH Terms
Aldosterone in vascular and metabolic dysfunction.
Luther JM
(2016) Curr Opin Nephrol Hypertens 25: 16-21
MeSH Terms: Adipocytes, Aldosterone, Animals, Blood Glucose, Blood Pressure, Coronary Circulation, Diabetic Nephropathies, Humans, Mineralocorticoid Receptor Antagonists, Muscle, Smooth, Vascular, Receptors, Mineralocorticoid, Vascular Endothelial Growth Factor Receptor-1
Show Abstract · Added November 30, 2015
PURPOSE OF REVIEW - This review will highlight recent developments in mineralocorticoid receptor research which impact aldosterone-associated vascular and cardiometabolic dysfunction.
RECENT FINDINGS - The mineralocorticoid receptor is also expressed in vascular smooth muscle and vascular endothelium, and contributes to vascular function and remodeling. Adipocyte-derived leptin stimulates aldosterone secretion, which may explain the observed link between obesity and hyperaldosteronism. Adipocyte mineralocorticoid receptor overexpression produces systemic changes consistent with metabolic syndrome. Ongoing studies with novel nonsteroidal mineralocorticoid receptor antagonists may provide a novel treatment for diabetic nephropathy and heart failure in patients with chronic kidney disease, with reduced risk of hyperkalemia.
SUMMARY - Ongoing research continues to demonstrate novel roles of the vascular and adipocyte mineralocorticoid receptor function, which may explain the beneficial metabolic and vascular benefits of mineralocorticoid receptor antagonists.
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12 MeSH Terms
Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.
Qi Y, Wang X, Rose KL, MacDonald WH, Zhang B, Schey KL, Luther JM
(2016) J Am Soc Nephrol 27: 646-56
MeSH Terms: Adult, Aldosterone, Cross-Over Studies, Epithelial Sodium Channels, Exosomes, Female, Humans, Male, Renin-Angiotensin System, Sodium, Dietary
Show Abstract · Added November 30, 2015
Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.
Copyright © 2016 by the American Society of Nephrology.
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3 Members
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10 MeSH Terms
Aldosterone modulates thiazide-sensitive sodium chloride cotransporter abundance via DUSP6-mediated ERK1/2 signaling pathway.
Feng X, Zhang Y, Shao N, Wang Y, Zhuang Z, Wu P, Lee MJ, Liu Y, Wang X, Zhuang J, Delpire E, Gu D, Cai H
(2015) Am J Physiol Renal Physiol 308: F1119-27
MeSH Terms: Aldosterone, Animals, Dual Specificity Phosphatase 6, Electrolytes, MAP Kinase Signaling System, Mice, Mice, Knockout, Models, Animal, Phosphorylation, Protein-Serine-Threonine Kinases, Signal Transduction, Sodium Chloride Symporters, Sodium Chloride, Dietary, Thiazides, Ubiquitination
Show Abstract · Added April 24, 2015
Thiazide-sensitive sodium chloride cotransporter (NCC) plays an important role in maintaining blood pressure. Aldosterone is known to modulate NCC abundance. Previous studies reported that dietary salts modulated NCC abundance through either WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline alanine-rich kinase) or WNK4-extracellular signal-regulated kinase-1 and -2 (ERK1/2) signaling pathways. To exclude the influence of SPAK signaling pathway on the role of the aldosterone-mediated ERK1/2 pathway in NCC regulation, we investigated the effects of dietary salt changes and aldosterone on NCC abundance in SPAK knockout (KO) mice. We found that in SPAK KO mice low-salt diet significantly increased total NCC abundance while reducing ERK1/2 phosphorylation, whereas high-salt diet decreased total NCC while increasing ERK1/2 phosphorylation. Importantly, exogenous aldosterone administration increased total NCC abundance in SPAK KO mice while increasing DUSP6 expression, an ERK1/2-specific phosphatase, and led to decreasing ERK1/2 phosphorylation without changing the ratio of phospho-T53-NCC/total NCC. In mouse distal convoluted tubule (mDCT) cells, aldosterone increased DUSP6 expression while reducing ERK1/2 phosphorylation. DUSP6 Knockdown increased ERK1/2 phosphorylation while reducing total NCC expression. Inhibition of DUSP6 by (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased ERK1/2 phosphorylation and reversed the aldosterone-mediated increments of NCC partly by increasing NCC ubiquitination. Therefore, these data suggest that aldosterone modulates NCC abundance via altering NCC ubiquitination through a DUSP6-dependent ERK1/2 signal pathway in SPAK KO mice and part of the effects of dietary salt changes may be mediated by aldosterone in the DCTs.
1 Communities
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15 MeSH Terms
Aldosterone, parathyroid hormone, and the use of renin-angiotensin-aldosterone system inhibitors: the multi-ethnic study of atherosclerosis.
Brown J, de Boer IH, Robinson-Cohen C, Siscovick DS, Kestenbaum B, Allison M, Vaidya A
(2015) J Clin Endocrinol Metab 100: 490-9
MeSH Terms: African Americans, Aged, Aged, 80 and over, Aldosterone, Angiotensin-Converting Enzyme Inhibitors, Asian Americans, Atherosclerosis, Cross-Sectional Studies, European Continental Ancestry Group, Female, Hispanic Americans, Humans, Male, Middle Aged, Mineralocorticoid Receptor Antagonists, Parathyroid Hormone, Renin-Angiotensin System
Show Abstract · Added September 19, 2017
CONTEXT - Aldosterone and PTH are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed.
OBJECTIVE - We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort.
DESIGN, SETTING, PARTICIPANTS - We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n = 5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements.
OUTCOME - Serum PTH concentration.
RESULTS - Higher aldosterone associated with higher PTH (β = 0.19 pg/ml per 1 ng/dl of aldosterone, P < .0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a stepwise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/ml, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β = -2.327 pg/ml per use of RAAS inhibitor, P = .006), when compared with the use of any non-RAAS inhibitor medication.
CONCLUSIONS - Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration. These results extend prior evidence from observational and intervention studies suggesting a potentially important and modifiable relationship between the RAAS and PTH in humans.
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17 MeSH Terms