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Impaired Regulation of Renal K⁺ Elimination in the sgk1-Knockout Mouse

Dan Yang Huang^*,, Peer Wulff, Harald Völkl^||, Johannes Loffing^¶, Kerstin Richter^*,#, Dietmar Kuhl, Florian Lang and Volker Vallon^*,#

Departments of *Pharmacology and Physiology I, University of Tübingen, Department of Clinical Neurobiology, University of Heidelberg, and Department of Biology, Chemistry and Pharmacy, Free University of Berlin, Germany; ^||Department of Physiology, University of Innsbruck, Austria; ^¶Institute of Anatomy, University of Zürich, Switzerland; and ^#Departments of Medicine and Pharmacology, University of California, San Diego and VAMCSD, San Diego, California.

Correspondence to: Dr. Volker Vallon, Division of Nephrology/Hypertension, Departments of Medicine and Pharmacology, University of California San Diego and VAMC, 3350 La Jolla Village Drive (9151), San Diego, CA 92161. Phone: 858-552-8585 ext. 5945; Fax: 858-642-1438, E-mail: vvallon{at}ucsd.edu

	Abstract

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ABSTRACT. Serum- and glucocorticoid-regulated kinase 1 (Sgk1) contributes to Na⁺ reabsorption in the aldosterone-sensitive distal nephron. Sgk1-knockout (sgk1-/-) and littermate wild-type mice (sgk1+/+) were used to test the importance of Sgk1 in renal elimination of K⁺. Intravenous application of K⁺ load under anesthesia increased plasma K⁺ concentration by 1.3 to 1.4 mM in both sgk1-/- (n = 6) and sgkl+/+ (n = 7) mice. However, the increase of absolute and fractional renal K⁺ excretion observed in sgk1+/+ was significantly blunted in sgk1-/- animals. Both groups of mice decreased or increased renal K⁺ excretion to a similar extent after a low (<0.03%) or high (5%) K⁺ diet for 6 d, respectively. In sgk1+/+, plasma K⁺ concentration was not significantly modified by either high or low K⁺ diet. In sgk1-/-, however, high K⁺ diet enhanced plasma K⁺ concentration by about 1.6 mM, despite an excessive increase of plasma aldosterone concentration reaching values about sixfold higher than in sgk1+/+. Electrophysiological and immunohistochemical studies under high K⁺ diet indicated that reduced epithelial Na⁺ channel ENaC and/or Na⁺/K⁺-ATPase activity in the aldosterone-sensitive distal nephron accounted for the impaired response in sgk1-/- and that an enhanced apical abundance of renal outer medullary K⁺ channel ROMK partly compensated for the defect. The acute and chronic regulation of renal K⁺ elimination involves Sgk1.

	Introduction

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Aldosterone is a potent stimulator of both, renal reabsorption of Na⁺ (1,2) and renal excretion of K⁺ (3). The key molecules mediating those functions are the epithelial Na⁺ channel ENaC (4,5) and the renal outer medullary K⁺ channel ROMK (6,7). Both are expressed in the aldosterone-sensitive distal nephron (5,8–10). The regulation of ENaC by aldosterone involves the serum- and glucocorticoid-regulated kinase 1 (Sgk1), which was originally cloned from rat mammary tumor cells as a glucocorticoid-sensitive gene (11,12) and from human HEPG2 cells as a cell volume–regulated gene (13). Sgk1 is transcriptionally upregulated by mineralocorticoids (14–20), and coexpression of Sgk1 increases Na⁺ channel activity in Xenopus oocytes expressing the renal epithelial Na⁺ channel ENaC (14–16,18–26). Coexpression of Sgk1 was also found to stimulate Na⁺/K⁺-ATPase (27,28). The significance of those effects for renal Na⁺ excretion in vivo is illustrated by observations in the sgk1-knockout mouse (29): during normal salt diet, no significant difference in BP and renal function has been detected between mice lacking the sgk1 gene (sgk1-/-) and intact littermates (sgk1+/+). However, during dietary salt restriction, sgk1-/- mice can not decrease sufficiently Na⁺ excretion despite exaggerated increase of plasma aldosterone concentration, decrease of GFR, and increased proximal tubular Na⁺ reabsorption, and the renal loss of NaCl eventually leads to a significant decrease of BP (29). The significance of Sgk1 for Na⁺ homeostasis and BP maintenance is further illustrated by the fact that certain polymorphisms of the sgk1 gene correlate with enhanced BP in twin studies (30,31).

Most recent experiments indicate that Sgk1 can be similarly involved in the regulation of ROMK (32). The coexpression of Sgk1 together with the Na⁺/H⁺ exchange regulating factor 2 (NHERF2) (33) enhances the abundance of heterologously expressed ROMK1 within the cell membrane of Xenopus oocytes, leading to the respective increase of K⁺ current (32). In the absence of NHERF2, the coexpression of Sgk1 did not significantly modify ROMK1 trafficking or function (14,32). The study presented here has been performed to test whether Sgk1 is important in the regulation of K⁺ excretion in vivo. To this end, renal excretion of K⁺ has been studied in the sgk1-/- mouse.

	Materials and Methods

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Generation of the sgk1-knockout mouse (sgk1-/-) has been described in detail elsewhere (29). Heterozygous sgk1-deficient mice were either inbred or backcrossed to 129/SvJ wild-type mice for two generations and then intercrossed to generate homozygous sgk1-/- and sgk1+/+ mice. Male and female sgk1-/- mice were used in the studies and compared with littermate sgk1+/+ mice of the respective gender. Mice were genotyped by PCR.

Acute Effects of Intravenous K⁺ Loading
Clearance experiments were performed in anesthetized mice as described previously (34). Briefly, mice were anesthetized with 100 mg/kg intraperitoneal Inactin (Research Biochemicals International, Natick, MA) and 100 mg/kg intramuscular ketamine. Body temperature was maintained at 37.5°C by placing the animals on an operating table with a servo-controlled heating plate. The trachea was cannulated and 100% oxygen was blown toward the tracheal tube throughout the experiment. The femoral artery was cannulated for BP measurement and blood sample withdrawal. The jugular vein was cannulated for continuous maintenance infusion (in mM: 111 NaCl, 30 NaHCO₃, 4.7 KCl, 2.25 g/dl BSA) at a rate of 500 µl/h. For assessment of GFR, [³H]-inulin was added to deliver 20 µCi/h. Urine was collected with a bladder catheter. After surgery, mice were allowed to stabilize for 60 min. Subsequently, to determine basal kidney function, a first 30-min urine collection period was performed. Blood samples (20 µl) were collected immediately before and after urine collections. After completion of the first collection period, K⁺ loading was initiated by replacing 250 µl/h of the maintenance infusion by a high K⁺ solution (in mM: 111 KCl, 30 NaHCO₃, 4.7 NaCl, 2.25 g/dl BSA). Thirty minutes after starting K⁺ loading, kidney function was reassessed by performing another 30-min clearance. Additional blood was withdrawn after this final period to measure plasma aldosterone concentration.

Chronic Effects of K⁺ Diets
Mice were placed in metabolic cages (Tecniplast Deutschland, Hohenpeissenberg, Germany) to assess urinary excretion of fluid, Na⁺ and K⁺, and body weight. To assure quantitative urine collection, metabolic cages were siliconized and urine was collected under water-saturated oil. Mice had free access to tap water and the indicated diets. Twenty-four-hour urine collections were performed during an adaptation period of 3 d on a standard Na⁺ and K⁺ diet (0.25% Na⁺; 0.95% K⁺). Mice were subsequently given a low K⁺ diet (0.25% Na⁺; <0.03% K⁺) for 6 d, which was followed by a high K⁺ diet (0.25% Na⁺; 5% K⁺) for another 6 d. Blood was taken after finishing the urine collection periods on the last day of a diet regimen by puncturing of the retrobulbar plexus under brief ether anesthesia. Volumes of 40 µl were withdrawn into heparinized tubes for analysis of plasma concentrations of K⁺. At the end of the high K⁺ diet, 160 µl were withdrawn for additional measurement of plasma aldosterone concentration. In a separate set of mice, the adaptation period on standard diet was followed by a low Na⁺ diet (0.015% Na⁺; 0.95% K⁺) and mice were placed in metabolic cages to determine urinary excretion of Na⁺ and K⁺ on days 2, 8, 16, and 36.

Determination of Plasma and Urine Concentrations
The plasma and urine concentrations of Na⁺ and K⁺ were determined with a flame-emission photometer (ELEX 6361; Eppendorf AG, Hamburg, Germany). Plasma concentrations of aldosterone were measured by RIA (Immunotech, Marseille, France).

Immunohistochemistry for ROMK and alphaENaC under High K⁺ Diet
After 6 d on a high K⁺ diet, kidneys of anesthetized mice were fixed by vascular perfusion with 3% paraformaldehyde and 0.05% picric acid and were processed for immunohistochemistry as described previously (9). After preincubation with 10% normal goat serum, cryostat sections (4 mm thick) were incubated overnight at 4°C either with a 1/200 dilution of an affinity-purified rabbit–anti-rat ROMK antibody (Alomone Labs, Jerusalem, Israel) or a 1/500 dilution of an affinity-purified rabbit–anti-rat alphaENaC antibody (35). Binding sites of the primary antibodies were revealed with a 1/1000 dilution of a Cy3-conjugated donkey anti-rabbit IgG (Jackson Immuno Research Laboratories, West Grove, PA). All antibodies were diluted in PBS/BSA 1%. For control of unspecific antibody binding, the primary antibodies were omitted or replaced by a nonimmune rabbit serum. The specificity of the ROMK antibody was confirmed by the fact that the antibody did not bind to cryosections of kidneys of ROMK-deficient mice, provided by Dr. Steven Hebert (36,37).

Electrophysiological Studies in Isolated-Perfused Cortical Collecting Ducts under High K⁺ Diet
Experiments were performed 6 d after starting the high K⁺ diet. Segments 0.1 to 0.3 mm in length were dissected and perfused following principally the method of Burg et al. (38) with modifications (39,40). The transepithelial voltage (PD) was measured by a high impedance electrometer (FD223, WPI, Science Trading, Frankfurt, Germany) connected with the electrode via an Ag/AgCl half cell as described (29).

Statistical Analyses
Data are provided as means ± SEM. All data were tested for significance by Student’s t test, and only results with P < 0.05 were considered statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Acute Effects of Intravenous K⁺ Loading
Clearance experiments were performed in seven female sgk+/+ mice and six littermate female sgk-/- mice pretreated with standard K⁺ diet (0.95%) and exhibiting no significant difference in body weight (26.9 ± 1.1 versus 25 ± 1.0 g, NS). In the first period of clearance experiments, no significant differences were observed between sgk1+/+ and sgk1-/- in mean arterial BP (104 ± 4 versus 100 ± 3 mmHg, NS), GFR (11.7 ± 1.5 versus 10.2 ± 1.0 µl/min/g body wt, NS), urinary flow rate (70 ± 10 versus 70 ± 8 nl/min/g body wt, NS), plasma Na⁺ concentration (129 ± 2 versus 132 ± 3 mM, NS), or absolute or fractional urinary Na⁺ excretion (9 ± 4 versus 15 ± 4 nmol/min/g body wt, NS; 0.6% ± 0.2% versus 1.1% ± 0.3%, NS). Likewise, no significant differences were observed under basal conditions for the plasma K⁺ concentration or the absolute or fractional renal excretion of K⁺ (Figure 1).

View larger version (19K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Influence of acute intravenous K+ loading (+K+) on plasma K+ concentration, absolute and fractional renal K+ excretion, and plasma aldosterone concentration in sgk1-/- and sgk1+/+ mice. n = 6 to 7. * P < 0.05 versus sgk1+/+.

Chronic Effects of K⁺ Diets
Experiments were performed in eight sgk1+/+ mice (four female, four male) and eight littermate sgk1-/- mice (four female, four male). Wild-type and knockout mice exhibited similar body weight under standard K⁺ diet (23.5 ± 1.4 versus 25.0 ± 1.5 g, NS). In both sgk1+/+ and sgk1-/-, low K⁺ diet lowered (19.6 ± 1.4 versus 20.7 ± 1.2 g, NS), and the subsequent high K⁺ diet partly restored body weight (22.4 ± 1.2 versus 22.4 ± 1.5 g, NS). Figure 2 illustrates the pattern of urinary K⁺ excretion during alterations of the diet from standard to low and high K⁺. Both sgk1+/+ and sgk1-/- mice significantly decreased urinary K⁺ excretion after K⁺ restriction and increased urinary K⁺ excretion during chronic K⁺ load. No significant differences were observed among groups. The plasma K⁺ concentration did not significantly change in neither group during chronic dietary K⁺ restriction (Figure 3). Moreover, plasma K⁺ concentration remained virtually constant in sgk1+/+ during chronic K⁺ loading. In contrast, plasma K⁺ concentration of sgk1-/- increased significantly on a high K⁺ diet. This increase occurred in sgk1-/- despite a dramatic increase of plasma aldosterone concentrations reaching values about sixfold higher than those in sgk1+/+ (Figure 3). In comparison, we have previously reported that plasma aldosterone concentrations are only modestly enhanced in sgk1-/- versus sgk1+/+ when the animals were fed the standard K⁺ diet used also in the study presented here (1.2 ± 0.2 versus 0.6 ± 0.1 ng/ml) (29). Comparing both experimental series, mean values for plasma aldosterone were higher under high versus standard K⁺ diet by about 44% in sgk1+/+ (confirming previous studies (41)) and by about 370% in sgk1-/-.

View larger version (25K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Influence of chronic dietary K+ restriction (low K+ diet) or K+ loading (high K+ diet) on urinary K+ excretion in sgk1-/- and sgk1+/+ mice. n = 8 each group.

View larger version (26K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Influence of chronic dietary K+ restriction (low K+ diet) or K+ loading (high K+ diet) for 6 d on plasma K+ concentration and of chronic K+ loading on plasma aldosterone concentration in sgk1-/- and sgk1+/+ mice. n = 8 each group.* P < 0.05 versus sgk1+/+.

View larger version (27K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Influence of chronic dietary Na+ restriction (low Na+ diet) on renal Na+ and K+ excretion in sgk1-/- and sgk1+/+ mice. n = 6 each group. * P < 0.05 versus sgk1+/+.

View larger version (69K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 5. Immunohistochemical detection of ROMK and alphaENaC in connecting tubule profiles at 6 d of K+ loading (high K+ diet) in sgk1+/+ and sgk1-/- mice. Representative stainings are shown from a total of 5 sgk1-/- and 4 sgk1+/+ mice, respectively.

View larger version (14K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 6. Amiloride-sensitive transepithelial potential difference (PD) in isolated perfused collecting ducts at 6 d of K+ loading (high K+ diet) in the absence (14 to 17 ducts in six to eight mice) (white bar) and presence (10 to 14 ducts in six to eight mice) (black bar) of 10 µM amiloride. * P < 0.05 versus sgk1+/+.

	Discussion

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In comparison, the impaired renal response in Sgk1-deficient mice under chronic K⁺ loading is revealed by a renal K⁺ excretion that is not different from Sgk1 wild-type mice under these conditions despite of markedly higher plasma concentrations of K⁺ and aldosterone, which are major stimuli of renal K⁺ excretion. This phenotype indicates an impaired response in renal K⁺ excretion in Sgk1-deficient mice to chronic K⁺ loading. Furthermore, the findings indicate that extrarenal clearance of K⁺ from plasma can not prevent an abnormal rise in plasma K⁺ concentration in Sgk1-deficient mice under chronic K⁺ loading. Finally, the enhanced plasma concentrations of both K⁺ and aldosterone can serve to normalize renal K⁺ excretion in Sgk1-deficient mice under chronic K⁺ loading provided that their influences are at least in part independent of Sgk1. These compensating mechanisms could not serve in Sgk1-deficient mice under conditions of acute K⁺ loading and thus resulted in lower K⁺ excretion, probably because differences in plasma concentrations of K⁺ and aldosterone between Sgk1-deficient and wild-type mice were not yet of sufficient magnitude.

How could an impaired regulation in renal K⁺ excretion in response to chronic K⁺ loading account for an increase in plasma K⁺ concentration in Sgk1-deficient mice when the renal K⁺ excretion measured over this period was not statistically different? It is important to remember that only 2% of total body K⁺ reside in the extracellular fluid compartment. On the basis of a total body K⁺ of a 70-kg man of 3.500 mmol or 50 mmol/kg, total body K⁺ of a mouse of 30 g is estimated to be about 1.500 µmol. Furthermore, gain from the extracellular compartment of an amount of K⁺ equal to only 0.7% of total mouse K⁺ content (approximately 10.5 µmol) can increase mouse plasma concentration of K⁺ by 30% (which is the difference observed between Sgk1-deficient and Sgk1 wild-type mice on high K⁺ diet in the study presented here). Taking into consideration that the mice on high K⁺ diet excreted about 1.200 µmol K⁺/d and further considering the possibility that full hyperkalemia may have developed in Sgk1-deficient mice over the initial 2 to 3 d (in which time about 2.500 µmol were excreted through the kidneys), a difference in renal K⁺ excretion between Sgk1-deficient and Sgk1 wild-type mice sufficient to explain a gain of 10.5 µmol in the extracellular fluid may have been too small to be detectable. Furthermore, aldosterone is one of the factors that contribute to extrarenal potassium homeostasis, including K⁺ uptake in muscle or K⁺ secretion in colon (42). Considering the possibility that these effects of aldosterone, like in the kidney, depend in part on Sgk1, impaired extrarenal K⁺ homeostasis may help to unmask an inadequate renal response of Sgk1-deficient mice in response to high K⁺ diet, simply because the burden on the kidney would be enhanced. It is important to remember, however, that in response to chronic changes in K⁺ intake, the kidney plays the dominant role to adjust K⁺ excretion whereas extrarenal mechanisms like the amount of K⁺ excreted in the feces, although affected, do not contribute significantly to overall K⁺ balance under conditions of normal kidney function (41–43). In other words, the observed 30% increase in plasma K⁺ concentration in response to a high K⁺ diet in Sgk1-deficient mice, which is accompanied by a marked increase in plasma aldosterone concentration and which is absent in wild-type mice, requires an impaired upregulation of renal K⁺ excretion.

The impaired ability of Sgk1-deficient mice to adequately upregulate renal elimination of K⁺ after K⁺ loading could have been due to impaired activities of apical ENaC and/or basolateral Na⁺/K⁺-ATPase as these two transport systems establish the electrochemical basis for apical K⁺ secretion through ROMK in the aldosterone-sensitive distal nephron. Both ENaC (14–25) and Na⁺/K⁺-ATPase (27,28) are stimulated by Sgk1, and Sgk1 deficiency indeed impairs appropriate upregulation of Na⁺ retention in that part of the nephron during salt restriction (29). Alternatively, defective K⁺ elimination may be secondary to a more direct effect of Sgk1 on renal K⁺ excretion, as Sgk1 has recently been shown to upregulate ROMK1 (32,44–46). Similar to what has been shown for ENaC (20,24,25), Sgk1 enhances the abundance of ROMK1 in the cell membrane of Xenopus oocytes (32,44,46). Beyond that, intriguing evidence points to a more direct effect of Sgk1 on ROMK1, as the coexpression of the kinase leads to a small but significant shift of the pH sensitivity of the channel (32,45).

Two observations, both made under chronic K⁺ loading, suggest a defect in ENaC and/or Na⁺/K⁺-ATPase rather than in ROMK as the dominant cause for the observed impaired regulation of K⁺ excretion in Sgk1-deficient mice. On the one hand, immunohistochemistry does not show decreased but enhanced abundance of ROMK channel protein in the apical membrane of the renal collecting system of Sgk1-deficient mice during high K⁺ diet. This observation does not rule out an in vivo stimulating effect of Sgk1 on ROMK channel trafficking to the cell membrane because the lacking influence of Sgk1 could be more than compensated for by the observed hyperkalemia and/or enhanced aldosterone plasma concentrations if these influences enhance apical ROMK abundance partially independent of Sgk1. The observation nevertheless suggests that the impaired regulation of renal K⁺ elimination in Sgk1-deficient mice is the result of mechanisms other than impaired ROMK expression and ROMK channel trafficking to the cell membrane. These mechanisms could include an altered pH sensitivity and thus activity of ROMK channels (32). However, it is further observed that the absolute and the amiloride-sensitive transepithelial potential difference in the collecting duct under high K⁺ diet is lower in Sgk1-deficient mice compared with Sgk1 wild-type mice pointing to a decreased activity of apical ENaC and/or basolateral Na⁺/K⁺-ATPase rather than apical K⁺ channel activity as the dominant cause to explain the impaired regulation of renal K⁺ elimination in Sgk1-deficient mice. A dominant defect in the apical K⁺ channel would be expected to increase rather than decrease the transepithelial potential difference in the collecting duct. In the light of renal K⁺ excretion in Sgk1-deficient mice on high K⁺ diet similar to wild type, the defect in apical ENaC and/or basolateral Na⁺/K⁺-ATPase appears to be compensated by increased plasma concentrations of K⁺ and aldosterone and a resulting enhanced apical abundance of ROMK.

In conclusion, Sgk1 deficiency impairs renal regulation of K⁺ elimination after an acute and a chronic K⁺ load. Thus, Sgk1 is not only required for adequate regulation of renal Na⁺ reabsorption during Na⁺ restriction, but also is important for the regulation of renal K⁺ excretion during K⁺ excess.

	Acknowledgments

 
This study was supported by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Center for Interdisciplinary Clinical Research) 01 KS 9602 and Deutsche Forschungsgemeinschaft (Va 118/7-2, La 315/4-4, La 315/5-1). The anti-alphaENaC antibody was provided by Dr. Bernard C. Rossier and Dr. Edith Hummler, Lausanne.

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