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【关键词】 hypokalemia
Department of Pharmacology, New York Medical College, Valhalla, New York
ABSTRACT
We used the patch-clamp technique to examine the effect of DOCA treatment (2 mg/kg) on the apical small-conductance K (SK) channels, epithelial Na channels (ENaC), and the basolateral 18-pS K channels in the cortical collecting duct (CCD). Treatment of rats with DOCA for 6 days significantly decreased the plasma K from 3.8 to 3.1 meq and reduced the activity of the SK channel, defined as NPo, from 1.3 in the CCD of control rats to 0.6. In contrast, DOCA treatment significantly increased ENaC activity from 0.01 to 0.53 and the basolateral 18-pS K channel activity from 0.67 to 1.63. Moreover, Western blot analysis revealed that DOCA treatment significantly increased the expression of the nonreceptor type of protein tyrosine kinase (PTK), cSrc, and the tyrosine phosphorylation of ROMK in the renal cortex and outer medulla. The possibility that decreases in apical SK channel activity induced by DOCA treatment were the result of stimulation of PTK activity was further supported by experiments in which inhibition of PTK with herbimycin A significantly increased NPo from 0.6 to 2.1 in the CCD from rats receiving DOCA. Also, when rats were fed a high-K (10%) diet, DOCA treatment did not increase the expression of c-Src and decrease the activity of the SK channel in the CCD. We conclude that DOCA treatment decreased the apical SK channel activity in rats on a normal-K diet and that an increase in PTK expression may be responsible for decreased channel activity in the CCD from DOCA-treated rats.
epithelial Na channels; K secretion; protein tyrosine kinase; hypokalemia
MINERALOCORTICOIDS HAVE BEEN shown to stimulate renal Na absorption and K secretion (2, 18, 23). The early effect of mineralocorticoids on Na transport is the result of stimulation of existing Na channels and Na-K-ATPase (4, 5, 17, 23), whereas the late effect results from increasing transcription of the epithelial Na channel (ENaC) and Na-K-ATPase (1). The mineralocorticoid-induced increase in K secretion has been shown to depend on Na transport (9). This indicates that mineralocorticoid-induced stimulation of K secretion is largely due to increases in the electrochemical driving force for K secretion. However, several studies have reported that mineralocorticoids stimulate the apical K conductance in the rabbit cortical collecting duct (CCD) (14, 15, 18). Moreover, the possibility that mineralocorticoids may have a direct stimulatory effect on apical K channels is supported by the observation that serum and glucocorticoid-induced kinase (SGK), which is stimulated by aldosterone (25), facilitates the membrane insertion of ROMK into the plasma membrane in Xenopus laevis oocytes (33). However, infusion of aldosterone did not increase the number of the apical ROMK-like SK channel (16). This suggests that aldosterone-mediated increases in K secretion may result from increases in the electrochemical driving force for K secretion rather than stimulation of apical K conductance. It is possible that the effect of aldosterone-SGK pathway on ROMK is suppressed in the native tubules.
We speculate that mineralocorticoid-induced increases in renal K excretion should mimic the effect of low-K intake and decrease plasma K. Our previous experiments have shown that a low-K intake increases Src family PTK (28, 29) which enhances the tyrosine phosphorylation of the ROMK channel (11) and facilitates the internalization of ROMK1 (12). Thus it is conceivable that decreases in plasma K induced by mineralocorticoids may stimulate the expression of Src family PTK, which decreases the number of SK channels in the cell membrane. This hypothesis is tested in the present study by investigating the effect of DOCA on the activity of SK channels in the CCD of the rat kidney.
METHODS
Preparation of CCDs. Pathogen-free Sprague-Dawley rats of both sexes (age 6 wk) were used in the experiments. The animals were purchased from Taconic Farms (Germantown, NY) and placed on a normal rat chow (1.1% wt/wt). The animals were divided into the experimental group that received DOCA injection (2 mg/kg body wt) for 2, 4, and 6 days and the control group that received oil injection. In a separate set of experiments, rats were kept on a high-K (HK) diet (10%) and received DOCA injection for 6 days. Rats were killed by cervical dislocation, and kidneys were removed immediately. Several thin slices of the kidney (<1 mm) were cut and placed on the ice-cold Ringer solution until dissection. The dissection was carried out at room temperature, and two watchmaker forceps were used to isolate the single CCD. To immobilize the tubules, they were placed onto a 5 x 5-mm coverglass coated with polylysine (Sigma, St. Louis, MO). The coverglass was transferred to a chamber (1,000 μl) mounted on an inverted Nikon microscope. The CCDs were superfused with HEPES-buffered NaCl solution, and the temperature of the chamber was maintained at 37 ± 1°C by circulating warm water surrounding the chamber. The method to patch the basolateral membrane of the CCD has been described previously (26).
Patch-clamp technique. An Axon200A patch-clamp amplifier was used to record channel current. The K current and the Na current were low-pass filtered at 1 KHz and at 50100 Hz, respectively, using an eight pole Bessel filter (902LPF, Frequency Devices, Haverhill, MA). Data were digitized by Axon interface 1200 and stored on the hard-drive of an IBM-compatible Pentium computer (Gateway 2000).We used the pClamp software system 6.04 (Axon Instruments, Burlingame, CA) to analyze the data. Channel activity was defined as NPo, and was calculated from data samples of 60-s duration in the steady state as follows
(1)
where ti is the fractional open time spent at each of the observed current levels.
Immunoprecipitation and Western blot analysis. Renal cortex and outer medulla were dissected and homogenized as described previously. The ROMK antibody was added to the protein samples (500 μg) harvested from renal cortex and outer medulla with a ratio of (4 μg/1 mg protein). The mixture was gently rotated at 4°C overnight, followed by incubation with 25 μl of protein A/G plus agarose (Santa Cruz Biotechnology) for an additional 2 h at 4°C. The tube containing the mixture was centrifuged at 3,000 rpm and the agarose bead pellet was mixed with 25 μl 2x SDS sample buffer containing 4% SDS, 100 mM Tris?HCl (pH 6.8), 20% glycerol, 200 mM dithiothreitol, 0.2% bromophenol blue. After the sample was boiled for 5 min, we loaded the supernatant to separate the proteins by electrophoresis on 10% SDS-polyacrylamide gels and transferred them to nitrocellulose membranes. The membranes were blocked with 5% nonfat dry milk in Tris-buffered saline (TBS) and rinsed and washed with 0.05% Tween 20-TBS buffer. We used ECL (Amersham Pharmacia Biotech) to detect the protein bands and the intensity of the corresponding band was determined with Alpha DigiDoc 1000 (Alpha Innotech, San Leandro, CA). The monoclone tyrosine phosphorylation antibody (PY20 or 4G10) was purchased from Upstate. For studying the expression of c-Src, protein samples extracted from renal cortex and outer medulla were separated by 8% SDS-polyacrylamide gels. The monoclone c-Src antibody was purchased from Transduction Laboratories (Lexinton, KY).
Experimental solution and statistics. The pipette solution contained (in mM) 140 KCl, 1.8 MgCl2, and 10 HEPES (pH 7.4) for studying K channel activity and 140 mM NaCl and 1.8 MgCl2 and 10 HEPES (pH 7.4) for studying ENaC. The bath solution for cell-attached patches was composed of (in mM) 140 NaCl, 5 KCl, 1.8 CaCl2, 1.8 MgCl2, and 10 HEPES (pH 7.4). Data are shown as means ± SE, and the paired Student's t-test was used to calculate the significance between the control and experimental groups. Statistical significance was taken as P < 0.05.
RESULTS
We first examined the activity of the apical SK channels in the CCD from control rats and animals treated with DOCA (200 μg/100 g) for 2, 4, and 6 days. The data summarized in Fig. 1 show that channel activity defined by NPo in the CCD was 1.3 ± 0.2 (n = 24) under control conditions and decreased significantly to 0.6 ± 0.2 (n = 22) from rats treated with DOCA for 6 days. We also examined the effect of DOCA treatment on ENaC activity in the CCD and confirmed that the activity of ENaC in the CCD in rats on a normal rat chow (0.5% Na) was almost absent and NPo was only 0.01 ± 0.07 (n = 14). DOCA treatment significantly increased Na channel activity from 0.01 ± 0.07 to 0.42 ± 0.10 (2 days, n = 11), 0.53 ± 0.10 (4 days, n = 11), and 0.49 ± 0.10 (6 days, n = 10), respectively (Fig. 2A). Figure 2B is a typical recording showing the activity of ENaC in the CCD from rats treated with DOCA for 0, 2, and 6 days, respectively.
After determining that DOCA increased the apical Na channel activity but decreased apical SK channel activity, we extended the study by examining the activity of basolateral K channels in the CCD from rats treated with DOCA for 6 days. Figure 3A is a recording demonstrating the activity of the basolateral 18-pS K channel in the CCD from control rats and from animals treated with DOCA for 6 days. From inspection of Fig. 3A, it is apparent that the activity of the basolateral 18-pS K channel was significantly higher in the CCD treated with DOCA than that observed in control animals. Also, we noticed that the amplitude of the basolateral K channel was larger in the CCD of the DOCA-treated rats than that of control animals at the same pipette holding potentials. This is presumably due to the hypopolarization of basolateral membrane in the CCD. Figure 3B summarizes results obtained from 12 patches showing that DOCA treatment increased the NPo from control value 0.67 ± 0.11 to 1.62 ± 0.14. Therefore, DOCA treatment significantly stimulated the basolateral K channel activity and apical ENaC activity but suppressed the apical SK channel activity.
An increase in ENaC activity induced by DOCA was expected to stimulate Na absorption and raise the electrochemical driving force for K across the apical membrane. This should enhance the K secretion and decrease the plasma K concentration (hypokalemia). This speculation was confirmed by measuring plasma K concentrations under control conditions and in DOCA-treated rats (Table 1). DOCA treatment did not alter plasma Na or Cl concentrations but significantly decreased the plasma K concentration from the control value, 3.80 ± 0.08 to 3.11 ± 0.2 meq (n = 5). Thus application of mineralocortocoids enhanced K secretion and led to decreases in plasma K concentrations.
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We previously demonstrated that low-K intake stimulates the expression of PTK (28, 29) and increases the tyrosine phosphorylation of ROMK (11) which enhances the internalization of ROMK-like SK channels in the CCD (12, 24). Thus we tested the hypothesis that decreases in apical SK channel activity following DOCA treatment were also due to the stimulation of PTK activity and tyrosine phosphorylation of ROMK channels. We used Western blot analysis to examine the expression of c-Src, a nonreceptor type of PTK expressed in the CCD, as a representative member of Src family PTK (12). Figure 4A is a typical Western blot showing that the expression of c-Src in the renal cortex and outer medulla was 85 ± 10% higher in rats receiving DOCA for 6 days than that in control animals (n = 4). DOCA treatment increased not only c-Src expression but also tyrosine phosphorylation of ROMK. Figure 4B is a typical Western blot demonstrating that DOCA treatment increased progressively the tyrosine phosphorylation of ROMK (n = 3). Although DOCA treatment had no effect on ROMK expression, tyrosine phosphorylation of ROMK in rats treated with DOCA for 6 days was 90 ± 10% higher than that of control rats.
To test the hypothesis that decreases in plasma K rather than DOCA are responsible for the DOCA-induced stimulation of Src-family PTK and decreasing SK channel activity, we examined the effect of DOCA on c-Src expression in the kidney from rats on a HK diet. Figure 5A is a Western blot showing that the expression of c-Src significantly decreases in renal cortex and outer medulla from rat on a HK diet (50 ± 5%) and DOCA-treated rats on a HK diet (40 ± 5%; n = 3) compared with the control animals. Moreover, the patch-clamp experiments have also demonstrated that channel activity (1.8 ± 0.4; n = 7) in the CCD from DOCA-treated rats on a HK diet is higher than that of control rats (1.19 ± 0.5), although the difference is not significant (Fig. 5B).
The notion that increases in PTK activity induced by DOCA treatment were responsible for suppression of apical SK channel activity in the CCD from rats receiving DOCA for 6 days was supported by experiments in which inhibition of PTK increased the activity of the apical SK channels. Figure 6A is a channel recording showing the effect of herbimycin A (1 μM) on the apical SK channels in the CCD from a DOCA-treated rat. It is clear that addition of herbimycin A increased channel activity. Figure 6B summarizes the effect of herbimycin A on apical SK channel activity in the CCD from rats treated with DOCA for 6 days, showing that inhibition of PTK increased NPo from 0.5 ± 0.1 to 2.1 ± 0.2 (n = 13). Thus inhibition of PTK increases the activity of ROMK-like SK channel activity in the CCD.
DISCUSSION
The main finding of the present study is that mineralocorticoid treatment decreased apical SK channel activity in rats on a normal-K diet. The similar observation has been reported by Palmer's study in which infusion of aldosterone decreased SK channel activity by 30% (16). In addition to ROMK-like SK channels, the Ca2+-dependent maxi K channels are also expressed in the CCD (3, 7, 21). However, we could not detect the maxi K channel activity in principal cells in the CCD from both control and DOCA-treated rats. It is possible that the maxi K channels were active only when tubule flow rate was high (13, 30, 31). Thus it is safe to conclude that the ROMK-like SK channel plays an important role in mediating K secretion at a normal tubule flow rate. Our finding that DOCA does not increase ROMK channel activity in the CCD is not consistent with the observation that DOCA treatment increases the apical K conductance in the isolated, perfused rabbit CCD in which mineralocorticoids augment the apical K conductance (14, 15, 18, 19). The discrepancy may be the result of different tissue preparations (split-open CCDs vs. isolated, perfused tubules) because several factors such as cross-talk mechanisms between Na-K-ATPase and apical K channels (22) may not be effective in the split-open tubules.
It is well established that apical K channel activity in the CCD is closely coupled with the basolateral Na-K-ATPase: stimulation of Na-K-ATPase increases, whereas inhibition of Na-K-ATPase decreases the apical K channel activity (14, 15, 27). Mineralocorticoid application is expected to stimulate the transepithelial Na transport and Na-K-ATPase. Thus it is conceivable that increases in Na-K-ATPase activity should lead to stimulation of apical SK channel activity. However, such a cross-talk mechanism may be more effective in the isolated, perfused tubules than in the split-open CCDs. However, even if such a mechanism may be effective in vivo and contribute to DOCA-mediated increases in apical K conductance, the effect of DOCA on apical K channels is the result of augmentation of Na-K-ATPase activity rather than a direct stimulation of SK channels.
It is possible that mineralocorticoids may stimulate the activity of maxi K channels and increase the apical K conductance in the rabbit CCD. Although we did not observe the Ca2+-dependent maxi K channel activity in principal cells of the CCD from control and DOCA-treated rats, we could not exclude the possibility that the mineralocorticoid-induced increases in maxi K channel activity are absent in nonperfused CCDs. Considering that maxi K channel activity may be flow dependent, the split-open tubule may not be proper preparation for studying the maxi-K channel activity. It has been demonstrated that Ca2+-dependent maxi K channels may also be involved in K secretion, especially when the tubule flow rate is high (30, 31). Furthermore, micropuncture study has shown that inhibition of the Ca2+-dependent maxi K channels suppressed the distal K secretion (G. Malnic, personal communication) in mice fed with a HK diet, which is known to stimulate mineralocorticoid secretion (1). Thus it is possible that increases in Ca2+-dependent maxi K channel activity induced by DOCA may contribute to increases in apical K conductance. In addition, voltage-gated K channels such as Kv1.3 are expressed and may be involved in K secretion in the CCD (32). Because SGK has been shown to stimulate the activity of Kv1.3 channels (6), it is possible that increases in voltage-gated K channel activity induced by SGK may also contribute to the aldosterone-mediated increases in K secretion.
The present study demonstrates that DOCA-induced stimulation of the renal K secretion is not the result of increases in ROMK-like SK channel activity. The observation that DOCA treatment significantly increases the activity of ENaC and the basolateral 18-pS K channels supports the notion that increases in the electrochemical driving force play an important role in mediating the DOCA-induced stimulation of renal K secretion. Stimulation of basolateral K channels leads to hyperpolarization of cell membrane potential which not only increases the driving force for Na entry but also decreases the driving force for K recycling across the basolateral membrane. Accordingly, K entering the cells via Na-K-ATPase would be secreted into the lumen to keep the intracellular K content constant. It has been reported that 916 days of DOCA treatment hyperpolarized the cell membrane potential such that it exceeded the K-equilibrium potential (20). Accordingly, basolateral K channels can serve as a route for K entering the cell across the basolateral membrane. In addition to 18-pS K channels, an intermediate-conductance and a large-conductance K channel are also in the basolateral membrane (8). Although we did not examine their activity, it is possible that both intermediate- and large-conductance K channels are also activated by DOCA treatment.
Increases in K secretion lower plasma K and cause hypokalemia. Thus DOCA treatment-induced decreases in ROMK-like SK channel activity act as a compensatory mechanism to prevent excessive K loss. Three lines of evidence indicate that DOCA treatment-induced decrease in SK channel activity was the result of activation of PTK-dependent signaling: 1) DOCA treatment stimulated c-Src expression and tyrosine phosphorylation of ROMK in the CCD from rats on a control K diet; 2) inhibition of PTK significantly increased the SK channel activity; and 3) DOCA did not decrease SK channel activity in the CCD from rats on a HK diet in which c-Src expression decreased. The effect of DOCA on c-Src expression is most likely the result of decreases in plasma K rather than a direct effect on PTK. This speculation was supported by two lines of evidence: 1) the expression of c-Src decreased in DOCA-treated rats on a HK diet; and 2) a significant increase in c-Src expression was observed in the kidney from rats treated with DOCA for more than 4 days. This is also consistent with the finding that there was no significant difference in plasma K in rats treated with DOCA for fewer than 4 days (Wei Y, Babilonia E, Sterling H, Jin Y, and Wang W-H, unpublished observations).
It has been shown that SGK stimulates the phosphorylation of ROMK and enhances the insertion of the ROMK channel into the plasma membrane in X. laevis oocytes (33). Moreover, deletion of SGK has been shown to impair the renal K secretion in response to HK intake (10). Because the expression of SGK increased in response to aldosterone (25), it is expected that aldosterone should increase the apical SK channel activity. However, infusion of aldosterone in rats has been shown to increase ENaC activity but have no effect on ROMK channel activity (16). Also, we observed that DOCA treatment did not increase the SK channel activity in the CCD from rats treated with DOCA for 2 days. Although the expression of c-Src in the kidney from rats treated with DOCA for 2 days was not significantly different from the control value, it is possible that DOCA treatment may stimulate the activity of PTK. It is also possible that the mechanism by which mineralocorticoids stimulate ROMK insertion in the cell model may be suppressed by a PTK-dependent signaling pathway. However, such a mechanism may be demonstrated in rats fed with a HK diet because a HK diet suppresses PTK expression.
Figure 7 is a model of principal cells illustrating a possible mechanism by which DOCA regulates the activity of the apical SK channel, ENaC, and basolateral 18-pS K channel. DOCA treatment stimulates the basolateral K channels and ENaC and increases the electrochemical gradient for K secretion which leads to an enhanced K secretion in the collecting duct. This leads to decreases in plasma K concentrations (hypokalemia). As a consequence, Src family PTK expression increases and tyrosine phosphorylation of ROMK channels is enhanced. Stimulation of tyrosine phosphorylation of ROMK facilitates the internalization of apical SK channels which would help in maintaining excessive K waste.
We conclude that mineralocorticoids increase ENaC and basolateral K channel activity but decrease apical SK channel activity by stimulation of tyrosine phosphorylation of ROMK channels.
GRANTS
The work is supported by National Institutes of Health Grant DK-47402 (W. H. Wang) and Dr. Y. Wei is supported by American Heart Association Scientific Development Award AHA0530092N.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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