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Modulation of Renal Calcium Handling by 11-Hydroxysteroid Dehydrogenase Type 2

Paolo Ferrari^*, Mario G. Bianchetti, Aurelie Sansonnens^* and Felix J. Frey^*

*Division of Nephrology and Hypertension and Division of Pediatric Nephrology, Department of Pediatrics, Inselspital, University of Berne, Switzerland.

Correspondence to Dr. Paolo Ferrari, Division of Nephrology and Hypertension, Inselspital, University of Berne, Freiburgstrasse 10, 3010 Berne, Switzerland. Phone: 4131-632-3142; Fax: 4131-632-9734;

	Abstract

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ABSTRACT. Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11-hydroxysteroid dehydrogenase type 2 (11HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THF+5THF)/THE as a parameter of 11HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THF+5THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 ± 10/7 versus 115/73 ± 8/6 mmHg; P < 0.001 for systolic; P < 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 ± 0.05 to 1.18 ± 0.04 mmol/L (P < 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 ± 3.6 to 31.9 ± 3.1 µmol/L GFR (P < 0.01). Fractional calcium excretion increased from 2.4 ± 0.3 to 2.7 ± 0.3% (P < 0.01) and was negatively correlated to the fractional sodium excretion during GA (R = -0.35; P < 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R = 0.66; P < 0.0001). Inhibition of 11HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule. E-mail: paolo.ferrari@insel.ch

	Introduction

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The mineralocorticoid aldosterone and the glucocorticoids cortisol in humans and corticosterone in rodents have the same in vitro affinity for the nonselective mineralocorticoid receptor (MR) (1). The MR is normally protected from glucocorticoid occupation by the enzyme 11-hydroxysteroid dehydrogenase (11HSD), which converts cortisol to the receptor inactive cortisone (2). Of the two kinetically distinct forms of 11HSD (3,4), the high-affinity, NAD-requiring 11HSD2 is preferentially found in cells of the distal kidney tubules expressing MR and has only dehydrogenase activity (4,5).

The molecular basis of the syndrome of apparent mineralocorticoid excess (AME), an autosomal recessive disorder producing a low renin life-threatening form of hypertension has recently been elucidated (6–8). AME results from overactivation of the MR by cortisol (9). Mutations in the gene of 11HSD2 cause renal sodium retention, urinary potassium wasting, low renin, and low aldosterone hypertension because of excess cortisol binding to the MR. In patients with AME, nephrocalcinosis is a feature commonly observed (8–10).

Alterations of calcium metabolism and parathyroid function, namely reduced concentration of serum ionized calcium (Ca²⁺), increased urinary Ca²⁺ excretion, and elevated circulating level of parathyroid hormone (PTH), have been reported in both essential hypertension (11,12) and primary aldosteronism (13,14). Serum Ca²⁺ increases rapidly after adrenalectomy in patients with aldosteronoma (13), suggesting a direct effect of the steroid hormone. The influence of the short-term administration of mineralocorticoids or glucocorticoids on the interdependence between renal excretion of sodium and Ca²⁺ was studied in adrenalectomized dogs by Massry et al. (15), who suggested that the mechanisms for sodium transport, which are affected by mineralocorticoids in the distal tubule, might be dissociated from the transport of Ca²⁺ or magnesium. Moreover, decreased tubular reabsorption of Ca²⁺ has been described in glucocorticoid-treated asthmatics (16). Bostanjoglo et al. (17) found that 11HSD2 and MR are expressed by cells of the distal convoluted tubule (DCT) as well as connecting tubule cells and principal cells of the collecting duct. Interestingly, the thiazide-sensitive Na-Cl cotransporter is also expressed in DCT cells and is known to influence Ca²⁺ transport (18,19).

The activity of the 11HSD2 is potently blocked in vivo and in vitro by glycyrrhetinic acid (GA), the active compound of liquorice by two mechanisms, direct competitive inhibition (20) and pretranslational inhibition (21). Thus, the administration of high doses of GA (22) and mutations in 11HSD2 are phenotypically identical. We therefore investigated in a prospective study with healthy volunteers whether inhibition of 11HSD2 activity by GA in vivo is able to induce significant changes in renal Ca²⁺ handling.

	Materials and Methods

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Subjects and Study Design
The effect of modulation of 11HSD2 activity in vivo by GA on renal Ca²⁺ handling was investigated in 20 healthy volunteers (age, 25 ± 4 yr; 13 men, 7 women). Inclusion criteria for the participants were age between 18 and 45 yr, BP < 140/90 mmHg, and normal renal and liver function. Pregnancy was excluded by -HCG assay. Subjects were not allowed to take any medication, including liquorice and oral contraceptives. All participants gave written informed consent to the study, which was approved by the local ethical committee. At baseline, demographic data and basic hematochemical parameters, including plasma renin and aldosterone, were obtained.

The subjects collected three separate 24-h urine samples at baseline without GA and, while on the same diet containing approximately 150 mmol/d of sodium, they ingested 500 mg/d of GA for 1 wk, during which they collected 24-h urines at days 1, 3, and 7 of GA as described previously (23). Body weight and office BP were recorded at all time points. For each urine volume, creatinine, sodium, potassium, and Ca²⁺ excretion were measured. Serum sodium, potassium, ionized Ca²⁺, and creatinine were also measured. A 24-h ambulatory BP recording was performed once during the baseline study period and on day 7 of the GA period. Plasma renin and aldosterone were measured once during baseline and at day 7 of GA.

Analysis of Serum and Urinary Cations
Direct ion-selective electrodes were used for the measurement of serum and urinary sodium and potassium and serum ionized Ca²⁺ as described previously (24). Serum-ionized Ca²⁺ was determined at the prevailing blood pH under anaerobic conditions (24). Serum and urinary creatinine and urinary Ca²⁺ excretion were assessed colorimetrically. Absolute Ca²⁺ excretion was expressed as a function of the GFR, expressed as urinary Ca²⁺ x volume/GFR, where GFR is urinary creatinine x volume/serum creatinine; therefore, the Ca²⁺ excretion/GFR = urinary Ca²⁺ x volume x serum creatinine/urinary creatinine x volume = urinary Ca²⁺ x serum creatinine/urinary creatinine (25). The values are expressed as µmol/L GFR. The fractional excretion of calcium (FECa) was calculated by the following formula: (urinary Ca²⁺/urinary creatinine)/(serum creatinine/serum ionized Ca²⁺) · 100. Similarly, fractional excretion of sodium (FENa) was calculated.

Urinary Steroid Analysis
The in vivo activity of 11HSD2 was estimated by the urinary ratio of excreted active cortisol (tetrahydrocortisol [THF]) to inactive cortisone (tetrahydrocortisone [THE]) metabolites (THF+5THF)/THE. Urine samples for THF, 5THF, and THE were analyzed by gas chromatography-mass spectrometry on a Hewlett-Packard gas chromatograph 6890 equipped with a mass selective detector 5973 as described previously (23,26).

Statistical Analyses
Differences between means were assessed by t test or ANOVA for analysis of continuous variables and by nonparametric analysis for variables that were not normally distributed. Analyses were performed using the Systat 9.0 (SPSS Inc, Chicago, IL) statistical software package. Values are expressed as mean ± SD.

	Results

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Serum electrolytes, 24-h urinary electrolyte excretion, and variables of 11HSD2 function at baseline and during GA administration are reported in Table 1. Baseline 11HSD2 activity was estimated by the (THF+5THF)/THE ratio in three separate random urine collections during the control period and was on average 0.94 ± 0.28, with an intraindividual variability of 11 ± 9%. Also, during baseline intraindividual coefficient of variation in urinary Ca²⁺ excretion was 9 ± 5%. Seven days of GA in a dose of 500 mg/d increased (THF+5THF)/THE ratio from the first day (Table 1). Urinary GA excretion was undetectable during baseline and averaged 1.3 ± 0.7 mg/d in urines collected on day 7. Urinary sodium excretion and sodium/potassium ratio tended to be lower at day 1 and day 3 of GA as compared with the corresponding values at baseline and increased again at day 7 of GA, suggesting mineralocorticoid escape (Table 1). Serum sodium increased from 136.5 ± 0.6 to 138.7 ± 0.7 mmol/L (F-ratio, 3.095; P = 0.05), and potassium decreased from 4.1 ± 0.1 to 3.7 ± 0.1 mmol/L (F-ratio, 29.6; P < 0.0001) during GA administration. Compared with baseline, there was a significant decrease in plasma renin (14.3 ± 10.9 versus 8.2 ± 6.4 ng/L; P < 0.05) and aldosterone (354 ± 179 versus 210 ± 132 pmol/L; P < 0.01) at day 7 of GA. Ambulatory BP was higher at day 7 of GA than at baseline (126/77 ± 10/7 versus 115/73 ± 8/6 mmHg; P < 0.001 for systolic; P < 0.05 for diastolic). There was a small but NS increase in body weight after 7 d of GA (from 70.3 ± 6.7 to 72.1 ± 6.7 kg).

View larger version (23K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Individual (and mean ± SD) serum ionized calcium during baseline conditions and after 1, 3, and 7 d of glycyrrhetinic acid (GA) administration (500 mg/d) in 20 healthy volunteers (P < 0.0001 by ANOVA versus baseline).

View larger version (22K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. (Top) Individual (and mean ± SD) calcium clearances in µmol/L GFR (P < 0.001 by ANOVA versus baseline) and (Bottom) fractional calcium excretions (P < 0.001 by ANOVA versus baseline) during baseline conditions and after 1, 3, and 7 d of GA administration (500 mg/d) in 20 healthy volunteers.

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Fractional excretion of calcium (FECa) as a function of fractional excretion of sodium (FENa). (Top) Regression line (dashed) and symbols (x) during baseline and regression line (solid) and symbols (•) during GA administration are shown separately; P < 0.0001 for the difference between the two slopes. (Middle) Relationship between FECa/FENa ratio and FENa (R = 0.89; P < 0.0001), with log-linear fit. (Bottom) Relationship between the FECa/FENa ratio and serum ionized calcium (R = 0.41; P < 0.01), with regression line and 95% confidence intervals. Data are from pooled results at baseline and during GA administration in 20 healthy volunteers.

View larger version (20K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Relationship between serum ionized calcium and serum potassium from pooled results at baseline and during GA administration in 20 healthy volunteers. Regression line with 95% confidence intervals (R = 0.66; P < 0.001).

	Discussion

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The higher urinary Ca²⁺ excretion observed during inhibition of 11HSD2 is consistent with the increased calciuria observed in both animals (27) and humans (28) after long-term mineralocorticoid administration, as well as with the higher Ca²⁺ excretion reported in patients with primary aldosteronism compared with that in normotensive control subjects (14,29). However, this increase in urinary Ca²⁺ excretion associated with mineralocorticoid excess does not seem due to direct effects of aldosterone. Indeed, the increase of urinary Ca²⁺ excretion requires volume expansion and the consequent "escape phenomenon," as neither animals submitted to chronic mineralocorticoid administration (27) nor humans (29) exhibit higher Ca²⁺ excretion rates when sodium intake is substantially restricted.

The increased urinary Ca²⁺ excretion in mineralocorticoid excess states could be due to reduced reabsorption of Ca²⁺ after a reduced reabsorption of sodium in aldosterone-insensitive proximal tubular sites, where sodium handling is closely connected with that of Ca²⁺ (30). In this case, the increased Ca²⁺ excretion would be the result of the "escape phenomenon" elicited by plasma volume expansion. Among the possible candidates for altered sodium transport in tubular sites proximal to the targets of mineralocorticoid action, the furosemide-sensitive Na-K-2Cl cotransporter in the thick ascending loop of Henle deserves consideration (31). When the function of this transporter is inhibited by furosemide or decreased by a genetic defect as is observed in Bartter syndrome, sodium loss is accompanied by increased potassium and Ca²⁺ loss (31,32), because Ca²⁺ transport passively follows that of sodium in this segment. As a result of hypercalciuria, nephrocalcinosis is frequently observed in patients with Bartter syndrome or in neonates treated with furosemide (33).

Micropuncture and clearance data suggest that the hypercalciuria of mineralocorticoid escape is mediated in the terminal nephron, because a higher FECa/FENa ratio in DOCA-escaped rats than in saline-expanded animals is observed (34). Interestingly, the addition of hydrochlorothiazide significantly reduced the FECa/FENa ratio in mineralocorticoid-escaped animals (34). This is in line with the present findings that inhibition of the 11HSD2 enzyme induced a significant increase in the calcium-to-sodium fractional excretion ratio, which persisted even when the fractional excretion of sodium returned to baseline values at day 7 of GA. The fact that 11HSD2 inhibition causes a dissociation of sodium and Ca²⁺ excretion accompanied by decrease serum Ca²⁺ and the inverse relation between FECa/FENa and serum ionized Ca⁺ (Figure 3) supports the hypothesis of a distal site of action. The significant difference in the slopes of the FECa-to-FENa relationship during control conditions and during mineralocorticoid excess (Figure 3), with the latter less than the control, is consistent with a distal site of action. Recent evidence showing immunohistochemical colocalization in the human distal convoluted tubule of the major renal sodium transporting proteins with proteins involved in transcellular Ca²⁺ transport (35) indicates that this region of the nephron plays a key role in the sodium-dependent changes of Ca²⁺ transport. There is evidence suggesting that salt transport by this nephron segment may also be regulated by aldosterone. Components of the mineralocorticoid receptor system, including the MR and the 11HSD2, have been found to be expressed by distal convoluted tubule cells along with the Na-Cl cotransporter, indicating that these cells are also targets of aldosterone action, possibly improving sodium recovery in low salt and volume states (17,36). In experimental animals, sites with the highest manifestation of the calcium-extruding machinery, including the recently discovered renal epithelial calcium channel, ECaC1 or CaT2 (37,38) were identified in the connecting tubule and distal convoluted tubule and colocalized with the epithelial sodium channel (39). Whether intracellular mineralocorticoid or glucocorticoid levels regulate expression or activity of the renal epithelial calcium channel (37,38), and by that modulate distal tubular Ca²⁺ reabsorption, is presently unknown. Regardless of the molecular mechanisms, inhibition of sodium transport, via Na-Cl cotransporter by thiazides or via ENaC by amiloride (40), is associated with increased transcellular Ca²⁺ reabsorption, inciting hypocalciuria (30). In humans with Gitelman syndrome, a genetic disorder caused by loss-of-function mutations of the Na-Cl cotransporter, hypocalciuria is also a characteristic feature (18,32). Thus, if mineralocorticoid excess was to foster sodium reabsorption in this segment of the nephron by increasing Na-Cl cotransporter expression or activity, hypercalciuria can be expected.

Another possible mechanism involved in mediating the increased Ca²⁺ excretion is the existence of a voltage-dependent Ca²⁺ movement across the cortical collecting duct (41). A lumen-negative transepithelial voltage exists across isolated cortical collecting ducts (42,43). This lumen-negative voltage is generated by the active sodium transport (42). Treatment of rabbits with DOCA stimulates sodium transport and increases the magnitude of the lumen-negative voltage across the cortical ducts (44). With lumen-negative voltages, a net Ca²⁺ secretion into the lumen is observed (41).

Ambulatory BP was higher at day 7 of GA than at baseline; it could therefore be argued that renal perfusion pressure per se may be an important determinant of Ca²⁺ excretion during mineralocorticoid excess. However, Brands and Hall (45) addressed this issue in an animal model of DOC-salt hypertension using dogs, whose renal perfusion pressure was maintained at control levels by a suprarenal silastic occluder. In the servo-controlled dogs, hypercalciuria was not different for the first 7 d of DOC than in the control DOC hypertensive dogs (45).

The question of long-term implications of hypercalciuria, particularly in growing children, regardless of the underlying cause, remains unanswered. One of the proposed consequences of hypercalciuria is nephrocalcinosis. The latter is a feature often observed in patients with the condition known as AME, resulting from a genetic defect in 11HSD2 activity (8–10). The present findings of increased urinary Ca²⁺ excretion during inhibition of 11HSD2 activity would therefore provide a potential explanation for the high prevalence of nephrocalcinosis in AME patients.

In our volunteers, serum Ca²⁺ levels were positively correlated with serum potassium concentration (Figure 4). This could suggest a possible pathogenetic link between potassium metabolism and abnormalities in Ca²⁺ handling. Indeed, a reduction in serum potassium concentration after potassium deprivation has been associated with increased Ca²⁺ excretion in humans (46). These changes could be mediated by extracellular volume expansion, because potassium depletion causes Na⁺ retention, even with suppressed aldosterone (47).

Inhibition of 11HSD2 activity is sufficient to significantly increase the fractional excretion of Ca²⁺ and decrease serum ionized Ca²⁺, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. Analysis of the relationship between renal sodium and calcium handling points to a distal tubular site of action of corticosteroids on renal calcium excretion.

	Acknowledgments

 
This work was supported in part by grants from the Swiss National Foundation for Scientific Research (Nr. 3100–58889) and the Cloëtta Foundation, Zurich, Switzerland. We thank Bernhard Dick and Claude Jenni for excellent technical assistance.

	References

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