Dietary K intake regulates the response of apical K channels to adenosine in the - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-22 08:08 |只看该作者 |倒序浏览 |打印

作者：Dimin Li, Yuan Wei, and Wen-Hui Wang作者单位：Department of Pharmacology, New York Medical College, Valhalla, New York 10595


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      【摘要】
   We used the patch-clamp technique to study the effect of adenosine on the apical 70-pS K channel in the thick ascending limb (TAL) of the rat kidney. Application of 1 µM cyclohexyladenosine (CHA), an adenosine analog, stimulated apical 70-pS K channel activity and increased the product of channel open probability and channel number ( NP o ) from 0.34 to 0.7. Also, addition of CGS-21680, a specific A 2a adenosine receptor agonist, mimicked the effect of CHA and increased NP o from 0.33 to 0.77. The stimulatory effect of CHA and CGS-21680 was completely blocked by H89, an inhibitor of protein kinase A (PKA), or by inhibition of adenylate cyclase with SQ-22536. This suggests that the stimulatory effect of adenosine analogs is mediated by a PKA-dependent pathway. The effect of adenosine analog was almost absent in the TAL from rats on a K-deficient (KD) diet for 7 days. Application of DDMS, an agent that inhibits cytochrome P -450 hydrolase, not only significantly increased the activity of the 70-pS K channel but also restored the stimulatory effect of CHA on the 70-pS K channel in the TAL from rats on a KD diet. Also, the effect of CHA was absent in the presence of 20-HETE. Inhibition of PKA blocked the stimulatory effect of CHA on the apical 70-pS K channel in the presence of DDMS in the TAL from rats on a KD diet. We conclude that stimulation of adenosine receptor increases the apical 70-pS K channel activity via a PKA-dependent pathway and that the effect of adenosine on the apical 70-pS K channel is suppressed by low-K intake. Moreover, the diminished response to adenosine is the result of increase in 20-HETE formation, which inhibits the cAMP-dependent pathway in the TAL from rats on a KD diet.
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adenosine receptor; adenosine 3',5'-cyclic monophosphate; protein kinase A; cytochrome P -450 hydroxylase; arachidonic acid; 20-hydroxyeicosatetraenoic acid
      【关键词】 regulates response channels adenosine ascending& ]2 p6 j8 y1 c5 m: [0 O
   ADENOSINE IS GENERATED FROM the hydrolysis of ATP via 5'-nucleotidase ( 17 ). Hypoxia, ischemia, and inflammation have been shown to enhance the adenosine generation ( 17, 22 ). Adenosine stimulates Na transport in the renal tubules ( 20 ). It has been shown that activation of the A 1 adenosine receptor increases the activity of the basolateral Na/HCO 3 symport and Na-phosphate transport in the proximal tubule ( 27 ). Also, adenosine has been reported to stimulate Na transport in A6 cells ( 19 ). Although the mechanism by which adenosine stimulates Na transport in A6 cells is not clear, it is possible that the effect of adenosine is mediated by the adenosine A 1 and A 2a receptors ( 19 ). Both the A 1 adenosine receptor and A 2 (A 2a and A 2b ) family adenosine receptor have been shown to be present in the thick ascending limb (TAL) ( 4 ); however, the role of adenosine in the regulation of the membrane transport in the TAL is not known.+ X3 A: a& X" ?$ p8 {( Q
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The TAL is responsible for the absorption of 20-25% filtered Na load and plays a key role in urinary concentrating ability ( 10 ). The Na transport in the TAL takes place by a two-step process: Na enters the cells across the apical membrane via the Na-K-Cl cotransport and leaves the cell across the basolateral membrane through Na-K-ATPase ( 10 ). The luminal K channels play a key role in K recycling, which is essential for maintaining the function of the Na-K-Cl cotransporter ( 11, 30 ). Inhibition of K recycling compromises the transepithelial Na transport in the TAL ( 11, 16 ). Three types of K channels, a 30-pS ( 32 ), a 70-pS ( 2 ), and a Ca 2  -dependent maxi K ( 15 ), are present in the apical membrane of the TAL. It is well established that the 70- and 30-pS K channels are mainly responsible for the apical K conductance ( 30 ). Moreover, ROMK gene product is an important component for both the 30- and 70-pS K channels ( 18 ). Thus the main goal of the present study was to investigate the effect of adenosine on the apical 70-pS K channel in the TAL and to investigate the influence of a K diet on the effect of adenosine on the K channels in the TAL.7 e2 D) t8 ], p) C& ~! S
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METHODS

Preparation of medullary TAL. Pathogen-free Sprague-Dawley rats (6 wk) were obtained from Taconic Farms (Germantown, NY), were kept on a normal rat chow, and given free access to water for 1 wk. Animal use was approved by the New York Medical College Animal Review Committee. The animals were then divided into the control group, which was fed with a normal-K diet (0.9-1%), and low-K group, which was kept on a K-deficient (KD; % U5 N1 |; A2 y

Patch-clamp technique. Patch pipettes were pulled with a Narishige model PP83 vertical pipette puller and had resistances of 4-6 M when filled with 140 mM KCl. The channel current was amplified by an Axon200A patch-clamp amplifier and was low-pass filtered at 1 kHz using an eight-pole Bessel filter (902LPF, Frequency Devices, Haverhill, MA). The current was passed through an Axon interface (Digitada1200) to digitize the signal, collected by an IBM-compatible Pentium computer (Gateway 2000) at a rate of 4 kHz, and analyzed using the pClamp software system 6.04 (Axon Instruments, Burlingame, CA). Channel activity was defined as NP o, a product of channel open probability ( P o ) and channel number ( N ). The NP o was calculated from data samples of 60-s duration in the steady state as follows5 Q" d) \1 @) `) p; t
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where t i is the fractional open time spent at each of the observed current levels. Because three types of K channels have been identified in the medullary (m)TAL, we measured the channel current at three different membrane potentials in each patch to estimate the conductance of the K channel in the patch.

Solution and statistics. The pipette solution contained (in mM) 140 KCl, 1.8 Mg 2 Cl, and 5 HEPES (pH 7.4). Cyclohexyladenosine (CHA) and CGS-21680 were obtained from Sigma, and H89 and SQ-22536 were purchased from Biomol (Plymouth Meeting, PA). DDMS was obtained from Dr. J. R. Falck's laboratory (Southwestern Medical Center at Dallas, TX). DDMS and 20-HETE were dissolved in ethanol, and the final concentration of ethanol was less than 0.1%, which had no effect on channel activity. The data are presented as means ± SE. We used a paired Student's t -test to determine the statistical significance. If the P value is

RESULTS# `, _$ {, _: M# w( X

We first examined the effect of CHA, an analog of adenosine, on the apical 70-pS K channel. Figure 1 is a channel recording showing that application of 1 µM CHA increased the channel activity defined by NP o from 0.34 ± 0.04 to 0.70 ± 0.1 ( n = 10). Although CHA increased the channel activity, the amplitude of the 70-pS K channel is not significantly altered. It is possible that the cell membrane potential in the TAL is primarily determined by basolateral K channel activity. Thus increases in the apical 70-pS K channel activity have a small effect on the cell membrane potential. CHA at low concentrations (

Fig. 1. Channel recording demonstrating the effect of 1 µM cyclohexyladenosine (CHA) on the apical 70-pS K channel in the thick ascending limb (TAL) from rats on a normal-K diet. The experiment was performed in a cell-attached patch and the holding potential was 0 mV. Top : time course of the experiment and 2 parts indicated by numbers are shown at fast resolution.% G5 f. r+ L  P

Fig. 2. Recording demonstrating the effect of 1 µM CGS-21680 (CGS) on the apical 70-pS K channel in the TAL from rats on a normal-K diet. The experiment was performed in a cell-attached patch and the holding potential was -40 mV. Top : time course of the experiment and 2 parts indicated by numbers are shown at fast resolution.
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Fig. 3. Channel recording demonstrating the effect of 1 µM CHA on the apical 70-pS K channel in the presence of H89 in the TAL from rats on a normal-K diet. The experiment was performed in a cell-attached patch and the holding potential was -10 mV. Top : time course of the experiment and 3 parts indicated by numbers are extended to demonstrate the channel details.

Fig. 4. Bar graph showing the effect of CHA (1 µM), H89 (1 µM), CHA H89, SQ-22536 (SQ; 10 µM), CHA SQ, CGS (1 µM), and CGS SQ on the apical 70-pS K channels. NP o, product of channel open probability and channel number. *Effect is significantly different from the control ( P
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After observing that CHA and CGS-21680 increased the apical 70-pS K channel in the TAL from rats on a normal-K diet, we examined the effect of CHA on the apical 70-pS K channel in the TAL from rats on a KD diet. Figure 5 is a channel recording demonstrating the effect of CHA on the apical 70-pS K channel in the TAL from rats on a KD diet for 7 days. We confirmed the previous finding that the channel activity was low in the TAL from rats on a KD diet ( NP o = 0.2 ± 0.03, n = 12). Moreover, from inspection of Fig. 5, it is apparent that addition of 1 µM CHA did not significantly increase the channel activity (CHA 0.26 ± 0.03, n = 5). Figure 6 is a dose-response curve of the 70-pS K channel to CHA in the TAL from rats on a normal-K diet ( ) and on a KD diet ( ). Stimulation of the adenosine receptor with 10 µM CHA increased channel activity by 130% to 0.8 ± 0.1 ( n = 3) in the TAL from rats on a control K diet. In contrast, 10 µM CHA failed to significantly increase the 70-pS K channel ( NP o = 0.30 ± 0.1, n = 3) in the TAL from rats on a KD diet.  u3 M% `. x" ~* ]) `
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Fig. 5. Recording demonstrating the effect of 1 µM CHA on the apical 70-pS K channel in the TAL from rats on a K-deficient (KD) diet. The experiment was performed in a cell-attached patch and the holding potential was 0 mV. Top : time course of the experiment and 2 parts indicated by numbers are shown at fast resolution.9 q+ ^1 C9 b1 o# v4 \  [9 R; ~

Fig. 6. Dose-response curve of CHA effect on the apical 70-pS K channel in the TAL from rats on a normal-K diet ( ) and on a KD diet ( ). Each point represents at least 3 experiments (patches). *Effect is significantly different from the control ( P
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We previously demonstrated that K restriction increases 20-HETE, which inhibits the apical 70-pS K channel ( 31 ). Thus we tested the possibility that the absence of the CHA effect on the apical 70-pS K channel was the result of increase in 20-HETE production in the TAL from rats on a KD diet. Therefore, we examined the effect of CHA in the presence of DDMS (5 µM), an inhibitor of cytochrome P -450 hydroxylase ( 21, 29 ). Figure 7 is a recording demonstrating the effect of the adenosine analog on the apical 70-pS K channel after inhibition of cytochrome P -450 hydroxylase in the TAL from rats on a KD diet. We confirmed the previous finding that inhibition of cytochrome P -450 hydroxylase increased the channel activity from 0.2 ± 0.03 to 0.49 ± 0.05 ( n = 12). Moreover, addition of 1 µM CHA stimulated the 70-pS K channel and increased the NP o from 0.49 ± 0.05 to 0.89 ± 0.1 ( Fig. 8 ). The stimulatory effect of CHA on the apical 70-pS K channel was still the result of activation of PKA because inhibition of PKA abolished the effect of CHA in the presence of DDMS. Figure 9 is a recording demonstrating the effect of CHA in the presence of DDMS. It is apparent, although inhibition of PKA did not significantly change the activity of the apical 70-pS K channel, that addition of CHA did not further increase the channel activity in the TAL from rats on a KD diet. The notion that an increase in 20-HETE production is responsible for the lack of stimulatory effect of adenosine on the 70-pS K channel in the TAL from rats on a KD diet is further supported by the finding in which application of 20-HETE almost completely abolished the effect of CHA on the apical 70-pS K channel in the TAL from rats on a normal-K diet. Figure 10 is a channel recording showing that 20-HETE (1 µM) decreased channel activity from 0.4 ± 0.05 to 0.15 ± 0.02. Moreover, in the presence of 20-HETE, 10 µM CHA failed to increase channel activity (0.18 ± 0.03, n = 4).2 O$ h. L. \0 p) ]% [( m: {
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Fig. 7. Recording demonstrating the effect of CHA (1 µM) on the apical 70-pS K channel in the presence of DDMS in the TAL from rats on a KD diet. The experiment was performed in a cell-attached patch and the holding potential was -30 mV. Three parts indicated by numbers are extended to show the detailed channel activity.

Fig. 8. Bar graph showing the effect of CHA (1 µM), DDMS (5 µM), CHA DDMS, CHA DDMS H89 on the apical 70-pS K channels. *Effect is significantly different from the control ( P

Fig. 9. Recording demonstrating the effect of CHA on the apical 70-pS K channel in the presence of DDMS and H89 in the TAL from rats on a KD diet. The experiment was performed in a cell-attached patch. Three parts indicated by numbers are extended to show the detailed channel activity.
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Fig. 10. Channel recording showing the effect of 1 µM 20-HETE and 10 µM CHA 20-HETE on the apical 70-pS K channel in the TAL from rats on a normal-K diet. The experiment was performed in a cell-attached patch, and the holding potential was -10 mV.& `$ P5 N! ]2 h
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DISCUSSION

The main finding of the present study is that stimulation of adenosine receptor increases the apical 70-pS K channel activity. Because the 70-pS K channel plays a role in K recycling across the apical membrane, which is essential for the function of the Na-K-Cl cotransporter, it is expected that adenosine should stimulate Na transport in the TAL. Three types of adenosine receptors, A 1, A 2a, and A 2b, have been shown to be expressed in the kidney ( 17, 22 ). Stimulation of A 1 receptor has been shown to cause inhibition of adenylate cyclase, decrease in cAMP concentrations, activation of PKC, and stimulation of phospholapase A 2 (PLA2) ( 26 ), whereas stimulation of A 2a or A 2b receptor has been reported to increase cAMP production and stimulate PKA ( 26 ). Recently, it has also been reported that stimulation of A 2a receptor increases 11,12- and 5,6-EET in the kidney ( 6 ). The RT-PCR analysis has detected A 1 and A 2b adenosine receptor mRNAs, whereas the band intensity for A 2a adenosine receptor mRNA is low in the TAL ( 28, 33 ). The possibility that application of adenosine could increase cAMP production in the TAL is also supported by experiments in which the exposure of the TAL to the adenosine analog caused increases in cAMP generation ( 1, 4 ).7 X. q6 X! t) Z4 [: r( t
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In the present study, we used CHA to stimulate adenosine receptor. Although CHA at low concentrations (

The physiological role of adenosine in the regulation of renal function has been well explored ( 20 ). Adenosine has been shown to regulate the glomerular filtration rate, renin release, and epithelial transport in the kidney ( 17 ). Also, adenosine has been demonstrated to play an important role in mediating tubuloglomerular feedback (TGF). Increase in Na delivery to the macular densa, a cell that has similar transport properties as that in the TAL, stimulates the adenosine release. Adenosine stimulates adenosine A 1 receptor in the afferent arteriole and causes vasoconstriction. The present study has further suggested that adenosine can enhance TGF not only by altering glomerular filtration rate but also by stimulating Na transport in the TAL. An increase in Na delivery to the TAL is expected to stimulate Na transport and increase ATP consumption. As consequence of increase in adenosine concentrations, adenosine stimulates the K recycling and possibly Na transport in the TAL. Therefore, adenosine can serve as a positive feedback mediator for Na transport.% V3 P; f: h- M
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Another finding of the present study is that the stimulatory effect of adenosine on the apical 70-pS K channel is almost absent in the TAL from rats on a KD diet. Two lines of evidence indicate that an increase in 20-HETE production is at least partially responsible for decreasing the stimulatory effect of adenosine on the 70-pS K channel in the K-restricted rats. First, inhibition of cytochrome P -450 hydroxylase restored the stimulatory effect of adenosine in the TAL from rats on a KD diet. Second, the stimulatory effect of CHA on the apical 70-pS K channel in the TAL was significantly diminished in the presence of 20-HETE. It is well established that AA is converted to 20-HETE via cytochrome P -450 -hydroxylase ( 23 ). We previously demonstrated that 20-HETE is present in the TAL and that the concentration of 20-HETE is significantly higher in the TAL from rats on a KD diet than those on a normal-K diet ( 13 ). Moreover, 20-HETE is a potent inhibitor for the apical 70-pS K channel and Na-K-Cl cotransporter ( 7, 31 ). Although the mechanism by which 20-HETE inhibits the 70-pS K channel is not completely understood, it is possible that the 20-HETE-induced inhibition is due to either blocking the 70-pS K channel directly or associated factors. The observation that the stimulatory effect of adenosine on the apical 70-pS K channel is almost absent in the TAL in the presence of 20-HETE suggests that 20-HETE suppresses the cAMP-dependent pathway and blocks the effect of CHA on the 70-pS K channel. This notion is supported by the experiment in which application of CHA failed to stimulate the 70-pS K channel in the presence of DDMS and H89. The possibility that eicosanoids can regulate protein kinase activity has been suggested by several studies. It has been reported that AA inhibits cAMP formation induced by vasopressin in the TAL ( 8 ), whereas it stimulates tyrosine phosphorylation ( 3 ). Moreover, it has been shown that EET activates Gs protein and Src family PTK ( 25 ). For instance, 11,12-EET has been reported to enhance PKA activity by increasing cAMP formation in the smooth muscle of renal vessels ( 6 ). Also, 14,15-EET has been demonstrated to activate PTK-dependent signaling ( 5 ).
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Dietary K intake has been shown to enhance the inhibitory effect of stimulating Ca 2  -sensing receptor on the apical 70-pS K channel. The enhanced response of K channels to the external Ca 2  is the result of increasing 20-HETE formation in the TAL ( 14 ). Now, we have shown that K restriction also leads to suppression of the stimulatory effect of adenosine on the apical 70-pS K channel activity. We speculate that K restriction may also attenuate the response of the apical K channels to hormones such as vasopressin. Further study is required to explore this possibility.# G! i* |( T1 H2 ~% c- ~9 l( o

We conclude that adenosine stimulates apical 70-pS K channel activity via a cAMP-dependent pathway in the TAL and that low-K intake diminishes the effect of adenosine on the apical 70-pS K channel.+ a: ~& a8 k# _) E" n( b5 y' i

GRANTS

The work is supported by National Institutes of Health Grants HL-34300 and DK-54983.
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