Evaluation of Renin and Soluble (Pro)renin Receptor in Patients with IPF. A Comparison with Hypersensitivity Pneumonitis

Introduction

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an unclear pathogenic mechanism. Components of the renin–angiotensin system (RAS) have a role in the pathogenesis of IPF, specifically, the aspartyl protease renin acts as a profibrotic factor in the lung. However, the concentration of the RAS components renin and soluble (pro)renin receptor (sPRR) have not been previously evaluated neither in serum nor in bronchoalveolar lavage fluid (BAL) of patients with IPF or chronic Hypersensitivity pneumonitis (cHP), a disease which may be confused with IPF.

Methods

The serum levels of renin [IPF patients (n = 70), cHP patients (n = 83), and controls (n = 26)] and sPRR [IPF (n = 28), cHP (37), and controls (n = 20)] were measured by ELISA. Renin was also quantified in BALs of IPF patients and controls by Western blot.

Results

We found that the levels of renin were higher in serum samples from IPF patients when compared with cHP patients and controls. Furthermore, BALs from IPF patients had more renin than BALs from controls. Unlike renin, the serum levels of sPRR were lower in IPF and cHP patients than in control individuals.

Conclusions

The high levels of renin in sera and BALs of IPF patients suggest that renin might play a major role in the pathogenesis of IPF. Results from BAL confirm that renin is produced locally in the lung. Serum levels of renin could be used to differentiate IPF from cHP.

     

Evidence for a Predominant Renal Secretion and Clearance of Inactive Plasma Renin,Studied by In Vivo Inhibition of Protein Synthesis,and Inhibition of Renal Tubular Protein Reabsorption

ABSTRACT

Inactive plasma renin is mainly secreted and eliminated by the kidneys in the mouse. The half-life of inactive plasma renin is 6 hours or less. The kidneys remove inactive renin from the circulation by glomerular ultrafiltration.     

Independent Change of Plasma and Tissue Renin in Response to Anesthetics

ABSTRACT

It was the purpose of this study to determine whether acute increases of endogenous plasma renin induced by administration of anesthetics cause simultaneous increases of the enzyme in aortic tissue of the rat. Administration of CO₂ did not alter plasma or tissue renin. Ether, Innovar and Nembutal increased active plasma renin and had variable effects on the inactive form of the enzyme. Only Innovar, a combination of droperidol and fentanyl, increased aortic renin. The active component of Innovar was shown to be droperidol, which also increased aortic renin in 24 hour nephrectomized animals. The increase of aortic renin was, therefore, independent of changes of circulating active or inactive renin. The increase of tissue renin following droperidol was rapid, suggesting activation of an inactive tissue renin.     

Determinants of the renin-angiotensin-aldosterone system in cirrhosis with special emphasis on the central blood volume

Objective. Several studies have shown activation of the renin-angiotensin-aldosterone system (RAAS) in cirrhosis. Although the activated RAAS may have several determinants, the system is often considered a surrogate marker of effective hypovolaemia. In this study we investigated the activity of the RAAS and its potential determinants with special focus on the central and arterial blood volume (CBV). Material and methods. Eighty-nine patients (Child class A/B/C: 19/41/29) and 32 controls were included in the study. All were given a haemodynamic examination with measurement of determinants of the RAAS, including the CBV. Circulating plasma renin concentrations were measured using an immunoradiometric assay. Results. Arterial renin concentrations were significantly higher in the patients than in the controls (p?0.003). Plasma renin correlated significantly with several indicators of liver dysfunction and splanchnic and systemic haemodynamics (r=???0.56–0.55), but only weakly with CBV (r=???0.25, p?0.02). In a multivariate regression analysis, plasma renin was determined by serum sodium, alkaline phosphatases and systolic blood pressure (p?0.04 to p?0.001). Conclusions. CBV correlates weakly with circulating renin, and activation of the RAAS can therefore only partly be considered as an indicator of central hypovolaemia. Mechanisms other than central hypovolaemia relating to the liver disease and portal hypertension contribute significantly to the RAAS activation.     

Influence of Angiotensin II (AII) and Angiotensin I (AI) on Renal Renin Synthesis and Release

ABSTRACT

This study examined the effect of exogenous AI and AII on renin synthesis and release. AII or AII+AI were given using osmotic minipumps, over a 7 day period to rats receiving oral Enalapril. Enalapril caused a marked increase in renin release and synthesis. AII abolished the rise in plasma and renal renin observed with Enalapril. AI had no inhibitory or stimulatory effect on renin release or synthesis in rats receiving Enalapril and AII.     

Direct renin inhibition with aliskiren normalizes blood pressure in Cyp1a1-Ren2 transgenic rats with inducible angiotensin ii-dependent malignant hypertension

IntroductionCyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1a1Ren2)], administered indole-3-carbinol (I3C) develop angiotensin (ANG) II-dependent hypertension due to hepatic expression of the Ren2 renin gene. Although AT₁ receptor blockade prevents the development of hypertension and normalizes the elevated arterial blood pressure of Cyp1-Ren2 rats, little information is available regarding the blood pressure and renal functional responses to direct inhibition of renin in this high circulating renin model of ANG II-dependent hypertension. This study was performed to determine the effects of acute direct renin inhibition with aliskiren on blood pressure and renal hemodynamics in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.MethodsMean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital- anesthetized male Cyp1a1-Ren2 rats during control conditions and after administration of the renin inhibitor, aliskiren (10 mg/kg, intravenous)ResultsRats induced with I3C had higher MAP (194 ± 7 versus 141 ± 2 mm Hg, P < 0.001), lower renal plasma flow (RPF; 2.47 ± 0.23 versus 4.17 ± 0.35 mL/min/g, P < 0.001) and lower glomerular filtration rate (GFR; 1.01 ± 0.07 versus 1.34 ± 0.06 mL/min/g, P = 0.01) than noninduced Cyp1a1-Ren2 rats (n = 5). Aliskiren administration decreased MAP (194 ± 7to136 ± 2 mm Hg, P < 0.001) and increased RPF (2.47 ± 0.23 versus 4.31 ± 0.20 mL/min/g, P < 0.001) in hypertensive but not in normotensive rats, without altering GFR.ConclusionsAcute renin inhibition with aliskiren normalizes MAP and RPF in Cyp1a1-Ren2 rats with malignant hypertension. The normalization of MAP and RPF after acute renin inhibition indicates that renin generated by expression of the Ren2 gene is responsible for the maintenance of malignant hypertension and the associated reduction in renal hemodynamic function in Cyp1a1-Ren2 rats.     

Heterogeneity of Glycosylation of Circulating Active and Inactive Renin

ABSTRACT

Concanavalin A chromatography was used to examine rat plasma and the incubation medium of rat renal cortical slices, the objective being to assess the heterogeneity of glycosylation of active and inactive renin. Inactive renin was measured by activation with trypsin. Concanavalin A chromatography could separate both active and inactive renin in the plasma into three forms, including the unbound form, the loosely-bound form and the tightly-bound form, thereby suggesting the presence of differently glycosylated forms of active and inactive renin in the plasma. Rat renal cortical slices secreted all these three forms of active and inactive renin, hence these forms are mainly of renal origin. These results suggest that differently glycosylated forms of active and inactive renin are released from the kidney into the blood circulation.     

High-dose spironolactone changes renin and aldosterone levels in acutely decompensated heart failure

BackgroundIn acutely decompensated heart failure (ADHF) patient's higher aldosterone levels correlate with worse postdischarge outcomes, suggesting that further modulation of the mineralocorticoid system during or immediately after hospitalization might favorably improve outcomes.Methods and resultsThis was an observational, retrospective secondary analysis of a study including 100 patients with ADHF. In that study 50 patients were submitted to spironolactone treatment (50–100 mg/day). A higher proportion of patients with renin levels above 16.5 pg/mL and aldosterone levels above 100 ng/dL were observed in subjects submitted to spironolactone treatment (44.7% vs. 66.7% and 56% vs. 64.7%, respectively, both p < 0.05). In the group of patients submitted to spironolactone treatment the proportion of patients with renin and aldosterone levels above the cutoff had a significant increase from baseline to day 3 (24–32% and 16–44%, respectively, both p < 0.05). Log renin and aldosterone were higher in patients with renin and aldosterone levels above the cutoff point (both p < 0.05).ConclusionsHigh-dose spironolactone added to standard ADHF therapy induces an additional increase in renin and aldosterone levels. Whether higher levels of renin and aldosterone due to the reactive response to full MRA still have prognostic value requires further investigation.     

Structure-Based Analysis of Single Nucleotide Variants in the Renin-Angiotensinogen Complex

BackgroundThe renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.ObjectivesTo identify SNVs that have functional and potentially damaging effects on the renin-angiotensinogen complex and to use computational approaches to investigate how SNVs might have damaging effects.MethodsA comprehensive set of all known SNVs in the renin and angiotensinogen proteins was extracted from the HUMA database. This dataset was filtered by removing synonymous and missense variants and using the VAPOR pipeline to predict which variants were likely to be deleterious. Variants in the filtered dataset were modeled into the renin-angiotensinogen complex using MODELLER and subjected to molecular dynamics simulations using GROMACS. The residue interaction networks of the resultant trajectories were analyzed using graph theory.ConclusionsThis research identified important SNVs in the interface of RAS and showed how they might affect the function of the proteins. For instance, the mutant complex containing the variant P40L in angiotensinogen caused instability in the complex, indicating that this mutation plays an important role in disrupting the interaction between renin and angiotensinogen. The mutant complex containing the SNV A188V in renin was shown to have significantly increased fluctuation in the residue interaction networks. D104N in renin, associated with renal tubular dysgenesis, caused increased rigidity in the protein complex comparison to the wild type, which probably in turn negatively affects the function of RAS.     

Effect of postural changes on aldosterone to plasma renin ratio in patients with suspected secondary hypertension

AimsTo study the influence of postural changes on aldosterone to renin ratio (ARR) in patients with suspected secondary hypertension and to evaluate the sensitivity and specificity of the recommended seated ARR compared to supine and upright ARR for primary aldosteronism screening.MethodsFifty-three hypertensive patients were prospectively hospitalized for secondary hypertension exploration (age: 51 ± 12, 66% males). After withdrawal of drugs interfering with renin angiotensin system, plasma aldosterone and direct renin concentration were measured in the morning, at bed after an overnight supine position, then out of bed after 1 hour of upright position and finally 2 hours later after 15 minutes of seating. Minimal renin value was set at 5 μUI/mL.ResultsReferring to ARR cut-off of 23 pg/μUI, the sensitivity of seated ARR was 57.1% and specificity was 92.3%. The negative and positive predictive values were 95.1% and 45.2% respectively. Compared to these results, a cut-off of 19 improved sensitivity to 85.7% with a specificity of 89.7%. Negative and positive predictive values were 98.3% and 41.1% respectively. Seated ARR mean value was lower than supine and upright ARR mean values, due to an overall increase in renin at seating compared to the supine position by factor 1.9 while aldosterone just slightly increased by factor 1.2. Seated ARR correlated to supine and upright ARR: correlation coefficients (r) 0.90 and 0.93 respectively (P < 0.001).ConclusionsCurrent recommended measurement of ARR in the seating position is fairly correlated to supine and upright ARR. A suggested cut-off value of 19 instead of 23 pg/μUI increased the discriminating power of this test.     

Cell and Molecular Studies of Renin Secretion

ABSTRACT

Renin secretion has been studied in the past at the level of the whole kidney, but the control of the genetic basis of renin synthesis is poorly understood. We have studied the regulation of renin gene expression in the fetus and also in the adult rat in response to angiotensin converting enzyme (ACE) inhibition with enalapril in the presence and absence of angiotensin II (AII). In the fetus, vascular smooth muscle cells of the renal afferent arteriole and feeder vessels contain renin mRNA and immunostain for renin. With maturation, these vessels progressively lose the capacity to synthesize renin, and only the juxtaglomerular cells retain this capacity in the adult. However, in response to ACE inhibition, the adult renal feeder vessels acquire the capacity to synthesize and secrete renin within 7 days. This effect is partially reversed with co-administration of AII.

In order to study renin biosynthesis and secretion at the cellular level, we have developed a new method of study of individual renin-secreting cells, the reverse hemolytic plaque assay (RHPA). Utilizing this method, we have demonstrated that ACE inhibition with enalapril increases the number of renin secreting cells by over 15-fold at physiologic calcium concentrations. Enalapril also induced a 3-fold increase in the amount of renin rleased as estimated by the area of the hemolytic plaques formed. Transmission electron microscopy (EM) of the renin-secreting cell at the center of a hemolytic plaque demonstrates modified vascular smooth muscle cells with cytoplasmic granules.

In summary, ACE inhibition stimulates renin mRNA accumulation and redistributes renal renin content toward that observed in early fetal life. AII inhibits renal renin mRNA accumulation. ACE inhibition increases the number of renin secreting cells as well as the amount of renin secreted by each cell. The individual renin secreting cell is a modified vascular smooth muscle cell with cytoplasmic secretory granules. Further studies of the cellular pathways for renin secretion can be provided by EM immunocytochemistry of the individual renin secreting cell.     

Partial Purification of a Prorenin Activating Enzyme in the Aortic Wall

ABSTRACT

The presence of a prorenin activating enzyme in the blood vessel wall may have important physiological implications. The putative enzyme may be involved with the endogenous production of active renin (a key enzyme in the vascular renin angiotensin system) or with the activation of circulating prorenin which had been taken up into the vessel wall. This study demonstrates the existence of a putative prorenin activating enzyme in the bovine aorta. Partial purification and characterization of the enzyme are described.     

Human Prorenin: Pathophysiology and Clinical Implications

ABSTRACT

Renin and prorenin, the latter after conversion to renin, are usually measured by indirect RIA using antibodies against angiotensin I. They can now also be measured by direct RIA using monoclonal antibodies reacting with total immunoreactive renin (renin plus prorenin) or with renin alone. Results of measurements in renal and peripheral venous plasma indicate that normally a large proportion of prorenin in plasma is of renal origin and they support the concept of separate pathways for prorenin and renin secretion by the JG-cells. Acute stimulation causes a prompt increase of plasma renin without any change in prorenin. During chronic stimulation both renin and prorenin are increased, in such a way that the ratio between the two is higher the stronger the stimulus. Thus, with acute stimulation only the release of stored renin appears to be increased (regulated pathway), whereas during chronic stimulation the synthesis and secretion of prorenin are also (constitutive pathway).

During pregnancy, in the early luteal phase of the menstrual cycle and after ovarian hyperstimulation with gonadotropins, a normal or somewhat elevated plasma level of renin is associated with a disproportionally high level of prorenin. This is an indication of extrarenal production of prorenin and in these conditions the ovary, probably corpus luteum, seems to be the main source. In most patients with renin-producing tumors plasma prorenin is also disproportionally high. In diabetes mellitus complicated by micro-angiopathy plasma prorenin is also elevated whereas renin is normal or even low. In diabetics with end-stage nephropathy we found no significant veno-arterial difference in prorenin across the kidneys, despite high circulating prorenin and a very low blood flow through these kidneys, suggesting that also in these patients part of the increased prorenin in plasma is of extrarenal origin.

Thus, measurements of prorenin in plasma in various pathological conditions may contribute to a better understanding of the physiological role of the renal and extrarenal renin-angiotensin systems.     

Cellular Mechanisms of Renin Release

ABSTRACT

The renin-angiotensin system plays a central role in salt and water balance and in the regulation of arterial blood pressure. The level of activity of this system is determined primarily by the rate at which the granulated juxtaglomerular cells (JG cells) secrete renin into the blood. Physiologically, renin secretory rate is controlled by a number of first messengers: afferent arteriolar transmural pressure or some function of it, such as stretch (the baroreceptor mechanism); solute transport in the macula densa segment of the nephron (the macula densa mechanism); catecholamines released from the renal nerves and the adrenal medulla (the β-adrenergic mechanism); extracellular concentrations of many organic and inorganic substances including angiotensin II, vasopressin, K, and Mg (1-3). In addition to these physiological first messengers, a number of pharmacological agents affect renin secretion (3).

It is an accepted principle of cellular biology that first messengers act by affecting the intracellular concentrations of only a few second messengers. The evidence that intracellular free ionic calcium, cyclic AMP, and cyclic GMP are second messengers in renin secretion has been reviewed in detail recently (4-9). These reviews are cited extensively, since space limitations precluded citing all the original literature.     

Effects of carvedilol and propranolol on circulatory regulation and oxygenation in cirrhosis: A randomised study

Background and aimsNewer studies suggest that carvedilol, a beta-blocker with a moderate anti-alpha-1 activity, is superior to propranolol in reducing the portal pressure and risk of variceal bleeding. The effect on arterial blood pressure is a matter of concern especially in decompensated patients.Aimsto assess potential differential effects of beta-blockers and beta-blockers with moderate anti-alpha-1 activity on selected haemodynamic, humoral, and respiratory characteristics in cirrhosis.MethodsPatients with cirrhosis and portal hypertension were randomised to receive carvedilol (n = 16) or propranolol (n = 13). Cardiac, systemic and splanchnic parameters along with oxygen saturation and plasma renin were measured at inclusion and after 3 months.ResultsArterial blood pressure, heart rate, and cardiac output decreased equally, central circulation time and systemic vascular resistance increased significantly but similarly. Central blood volume, plasma volume and arterial compliance were unaltered. The QT_c interval and renin levels decreased in the carvedilol group, however not significantly different from the propranolol group. Arterial oxygen saturation and alveolar arterial oxygen gradient remained constant in both groups. Hepatic venous pressure gradient decreased equally in the carvedilol and propranolol groups (−17% and −20%, non significant).ConclusionsSystemic haemodynamics and pulmonary effects of carvedilol and propranolol are modest and this study could not demonstrate any significant difference between the two treatments.     

Effects of cilnidipine on sympathetic nerve activity and cardiorenal function in hypertensive patients with type 2 diabetes mellitus: Association with BNP and aldosterone levels

AimsHypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus.MethodsIn 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated.ResultsSwitching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker.ConclusionsIn 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin–angiotensin–aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.     

Antihypertensive effect of rhizome part of Acorus calamus on renal artery occlusion induced hypertension in rats

ObjectiveThe rhizomes part of Acorus calamus (AC) having the calcium inhibitory effect and diuretic activity which may potentiate Na+ excretion in hypertension induced by occlusion of renal artery. Therefore this study was aimed to investigate the effect of AC on experimentally induced hypertension.MethodsHypertension in rats was induced by clamping the left renal artery for 4h by arterial clamp (2K1C). At the end of experiment animal were anesthetized with ketamine (50 mg/kg). Carotid artery was cannulated which was connected to pressure transducer for estimation of blood pressure.ResultsEthyl acetate extract of Acorus calamus rhizomes (EAAC) treated rats that underwent hypertension, demonstrated significant (P < 0.01) lower systolic blood pressure and diastolic blood pressure when compared with 2K1C rats indicated blood pressure lowering activity. Plasma renin activity was significantly (P < 0.05) decreased in EAAC treated rats compared to 2K1C rats. EAAC treated rats that underwent hypertension demonstrated significant (P < 0.01) lower mean blood urea nitrogen and creatinine when compared with 2K1C rats. Lipid peroxidation was significantly (P < 0.001) decreased, where as nitric oxide level in tissue was significantly elevated in EAAC treated rats. Antioxidant enzymes like glutathione, superoxide dismutase and catalase were significantly (P < 0.05, P < 0.01, P < 0.001) increased in EAAC treated rats when compared to 2K1C rats.ConclusionsIn conclusions, EAAC treatment attenuated renal artery occlusion induced hypertension via nitric oxide generation and decreases the plasma renin activity.     

Characterization of N-Linked Oligosaccharides Attached to Human Renin Expressed in COS Cells

ABSTRACT

To study the role of N-linked oligosaccharides attached to human renin, we generated three kinds of glycosylation-deficient renins in which one or both of two putative N-glycosylation sites was eliminated by amino acid replacement using site-directed mutagenesis. Examination of the three mutant renins (Asn-5 to Ala, Asn-75 to Ala, and both Asn-5 and -75 to Ala) expressed in COS cells demonstrated that both putative sites were certainly glycosylated with heterologous N-linked oligosaccharides. Moreover, the oligosaccharide chain attached at Asn-5 was different from that attached at Asn-75 in its molecular size. In addition, the secreted amount of the three mutant renins were different from one another, although the mutant and wild-type renins had practically the same specific activity. Our results suggest that the N-linked oligosaccharides have no effect on the enzymatic activity, but play an important role in stable secretion of human renin.     

Safety and efficacy of nesiritide in pediatric heart failure

BackgroundWe hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal function in pediatric patients.Methods and ResultsWe analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 mcg·kg·min without a bolus and titrated to a maximum of 0.03 mcg·kg·min, in 0.005-mcg·kg·min increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly (P = .001). Urine output increased significantly on Days 1 and 3 (P ≤ .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL (P ≤ .001). In the substudy, aldosterone levels decreased from 37.5 ± 57.1 to 20.5 ± 41.9 ng/dL (P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension.ConclusionsNesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.     

Hypertension in a patient with medullary sponge kidney: A case report

Rationale:Medullary sponge kidney (MSK) is a congenital renal disorder characterized by recurrent nephrolithiasis or nephrocalcinosis. Recently, it has been found that MSK can be also combined with other diseases, such as primary aldosteronism and Beckwith-Wiedemann, but whether it is associated with secondary hypertension remains unknown.Patient concerns:A 22-year-old hypertensive female presented to our hospital characterized by hypokalemia and hypertension.Diagnosis:The laboratory examination showed secondary aldosteronism. And the common causes for secondary aldosteronism include renal artery stenosis, glomerulonephritis, lupus nephropathy, and diabetic nephropathy, all of which were excluded except MSK.Interventions:She was treated with angiotensin-converting enzyme inhibitors.Outcomes:Her blood pressure, serum potassium, and plasma renin levels were reversed after treatment with angiotensin-converting enzyme inhibitors.Lessons:We presumed that MSK may be associated with secondary hypertension, and the mechanism may be the activation of the renin-angiotensin-aldosterone system.