Role of PKC and calcium in modulation of effects ofangiotensin II on sodium tra - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:35 |只看该作者 |倒序浏览 |打印

作者：ZhaopengDu, WilliamFerguson,  TongWang作者单位：Department of Cellular and Molecular Physiology, YaleUniversity School of Medicine, New Haven, Connecticut 06520-8026 ; n: x1 Z. j0 O0 D

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      【摘要】) R: j' m7 d9 F0 ]; Q! E
   It has been well documentedthat low concentrations of ANG II (10 11 to10 10 M) stimulate, whereas high concentrations of ANG II(10 8 to 10 5 M) inhibit Na transport in proximal tubules of rat and rabbit kidneys. Measured ANGII concentration in proximal tubular fluid is in the nanomolar range.In the present study, we investigated the role of PKC, intracellularCa 2 , and cAMP in modulating the effects of luminal ANG IIon Na absorption by microperfusion techniques in rabbitsuperficial segment of proximal tubules in vitro. We confirmed that ANGII (10 9 M) had no change on fluid absorption( J v ); however, fluid absorption increasedsignificantly when 10 9 M ANG II and3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester (TMB-8), ablocker of intracellular calcium mobilization, were added together. Incontrast, ANG II significantly decreased J v whenPKC was inhibited. When 10 9 M ANG II was present togetherwith 1-(5-isoquinolinesulfonyl)-2-mehtylpiperazine and TMB-8, nosignificant change of J v occurred. Inhibition of endogenous cAMP activity by a PKA inhibitor did not change either basalor ANG II-stimulated fluid absorption. Our results indicate that ANG IIregulates Na absorption by a cAMP-independent mechanismand that PKC and intracellular calcium both play a critical role inmodulating the effects of physiological concentration of ANG II onproximal tubule transport. Balance between these two cytosolicmessengers modulates the effects of ANG II on fluid absorption in theproximal tubule.
      【关键词】 Na transport proximal tubule microperfusion$ \  T; o. l. n6 a
   INTRODUCTION/ r/ [) S: ^; R; Q
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ANG II IS AN IMPORTANT HORMONAL regulator of Na and HCO 3 − transport in the proximal tubule. ANG II receptors are expressed onboth the apical and basolateral side of the proximal tubule ( 2, 3 ), and it has been shown to be produced locally and secretedinto the tubule fluid ( 17 ). ANG II has biphasic effects onNa and HCO 3 − transport in proximaltubules. Low concentrations (10 11 to 10 10 M) stimulate, whereas high concentrations (10 8 to10 5 M) inhibit Na transport in both rats andrabbits ( 6, 11, 20, 21 ). Blocking ANG II receptorssystemically decreases Na and HCO 3 − absorption in proximal tubules of rat kidney ( 13 ), whichindicates that endogenous ANG II upregulates Na andHCO 3 − absorption in the kidney. This is consistentwith the reported concentrations of ANG II in the plasma in thepicomolar range, which stimulates Na absorption( 17 ). In contrast, studies of ANG II concentrations in theproximal tubule fluid have detected levels in the nanomolar range, aconcentration that has no net changes on Na absorption( 11, 20, 21 ). It was reported that picomolar concentrations of ANG II stimulate PKC activity (no increase in cellCa 2  ) but high concentrations (10 8 to10 6 M) of ANG II increase cell Ca 2  and thatnanomolar concentrations of ANG II increase PKC activity andintracellular Ca 2  mobilization in the primary culturedrabbit renal proximal tubule cells ( 10 ). In the presentstudy, we examined the functional role of cAMP, PKC, and intracellularCa 2  in modulating the effect of ANG II on Na absorption in proximal tubules of rabbit kidney in vitro. Our resultsshow that Na transport is not inhibited by endogenouscAMP, whereas both PKC and cytosolic Ca 2  modulate theeffects of the nanomolar concentration of ANG II. Dual effects of ANGII of either stimulation or inhibition of transport may be the resultof different levels of Ca 2  and PKC activation in proximaltubule cells.' w! m2 R; B5 D, X. f+ Y) \3 w7 q

MATERIALS AND METHODS* {4 j8 _4 [) U* U
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Superficial proximal convoluted tubules (S 2 segments) were dissected and perfused in vitro by using conventionalmethods ( 9 ). Briefly, kidneys from adult female NewZealand white rabbits weighing 2-3 kg were removed and cut intocoronal slices. Individual tubules were dissected in cooled (4°C)Hanks' solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO 4, 0.33 Na 2 HPO 4, 1 MgCl 2, 10 Tris · HCl, 0.25 CaCl 2, 2 glutamine, and 2 L -lactic acid. Thesolution was bubbled with 100% O 2 and had a pH of 7.4.

S 2 segments of the proximal tubules were perfused with anultrafiltrate-like solution containing (in mM) 125 NaCl, 22 NaHCO 3, 1 CaCl 2, 1.2 MgSO 4, 2 glutamine, 2 lactic acid, 10.5 glucose, 5 KCl, and 1.2 phosphoric acid.A similar solution containing (in mM) 101 NaCl, 22 NaHCO 3,1 CaCl 2, 1.2 MgSO 4, 2 glutamine, 2 lactic acid,10.5 glucose, 5 KCl, 1.2 phosphoric acid, and 32.5 HEPES was used asbath medium. Perfusate and bath solutions were bubbled with 95%O 2 -5% CO 2 and had a pH of 7.4. Osmolalities of the bath and perfusate were adjusted to 300 mosmol/kgH 2 O bythe addition of either H 2 O or NaCl. The bath solution alsocontained 3 g/dl albumin. Bath fluid was continuously changed at a rate of at least 0.5 ml/min to maintain the constancy of pH and bath osmolality.

ANG II and several inhibitors were added to the luminal solutions. Alltubules were perfused at a rate of 10-20 nl/min at 37-38°Cin a 1.2-ml temperature-controlled bath. The first period of collectionbegan after an equilibration time of 30-60 min. Net fluid volumeabsorption ( J v ) was measured with[methoxy- 3 H]inulin. The extensively dialyzed(methoxy- 3 H)-inulin was added to the perfusate at aconcentration of 30 µCi/ml as a volume marker. For each experimentalperiod, three timed collections of tubular fluid were made, the volumeof the perfusate and collected samples were measured in a constant-bore glass capillary, and [ 3 H]inulin concentrations in thosesamples were determined in a liquid scintillation counter (modelLS5801; Beckman).7 z* K/ K" _9 ?# W+ a" Y
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The rate of net fluid reabsorption was calculated according to thefollowing equation: J v = V o V L, whereV L is the measured rate of fluid collection andV o = V L (IN L /IN o ). IN L /IN o isthe ratio of radioactive inulin of collected and original perfusionfluid. The rates of fluid absorption were expressed per millimeter ofthe proximal tubule.6 y0 u! _: h9 R  S+ d
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ANG II was purchased from Peninsula Laboratories (Belmont, CA), and[ 3 H]inulin was purchased from DuPont-New England Nuclear(Boston, MA). KT-5720 was purchased from Calbiochem (La Jolla, CA) and 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester (TMB-8), 1-(5-isoquinolinesulfonyl)-2-mehtylpiperazine (H-7), and all other chemicals were obtained from Sigma (St. Louis, MO).

All data were presented as means ± SE. Student's t -test was used to compare control and experimental groups.The ANOVA test was used for comparison of several experimental groupswith a control group. The difference between the mean values of anexperimental group and a control group was considered significant if P+ p5 z1 B0 B2 O- p0 |1 i

RESULTS- c4 J( W1 }) q. e; t

Effect of luminal ANG II on fluid absorption. In the first series of experiments, we confirmed that a lowconcentration of ANG II stimulates fluid absorption in theS 2 segment of the proximal tubule in vitro, as previouslyobserved in the rat in vivo ( 12, 21 ). Proximal tubuleswere microperfused with an ultrafiltrate-like solution containing125 mM NaCl and 22 mM NaHCO 3. Under these conditions,volume reabsorption ( J v ) results predominantlyfrom net Na absorption.9 `9 K1 v" a! ^8 s2 z- f
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As shown in Table 1 and Fig. 1, the addition of 10 11 M ANG II to the luminal perfusion solution resulted in significantstimulation of J v. J v increased by 127.8%, from 0.36 ± 0.02 to 0.82 ± 0.12 nl · min 1 · mm 1, P 9 M ANG II had no effect on fluid absorption. J v was 0.36 ± 0.02 nl · min 1 · mm 1 in control and was 0.32 ± 0.03 nl · min 1 · mm 1 in the presence of ANG II (10 9 M). These findings are inagreement with previous results that 10 11 M ANG IIstimulates Na absorption, whereas 10 9 M ANGII fails to affect transport of fluid ( 12, 21 ).
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Table 1. Effects of ANG II on fluid absorption in proximal tubules
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Fig. 1. Effects of luminal ANG II (AII) on fluid absorption( J v ) in proximal tubules. ANG II was added tothe luminal perfusate at concentrations of 10 11 and10 9 M, respectively. Control, without ANG II in theperfusate.

Effect of PKA inhibitor and ANG II on proximal tubule fluidabsorption. On the basis of the observation that ANG II decreases cAMPproduction and stimulates Na /H exchange(NHE), it was reported that ANG II increases the Na andHCO 3 − reabsorption rate by inhibition of cAMP, whichinhibits NHE ( 15 ). It was also demonstrated that ANG IIstimulates proximal tubule transport by a cAMP-independent mechanism( 4 ). Although a decrease in cAMP production would reduceits inhibitory effect on NHE, resulting in increased Na and HCO 3 − absorption, it is not known whether NHEactivity is inhibited by endogenous cAMP under physiological conditions. Therefore, a membrane-permeant PKA specific inhibitor, KT-5720, was used to examine the endogenous cAMP activity in the absence and presence of ANG II ( 1 ). As shown in Fig. 2 and Table 2, the addition of the PKA inhibitorKT-5720 at concentrations of 500 nM had no significant effect on J v compared with the control group (0.36 ± 0.05 vs. 0.38 ± 0.04 nl · min 1 · mm 1 ).A similar concentration has been reported by other laboratories ( 8, 16 ) to inhibit cAMP in proximal tubule cells. Thisresult indicates the net Na absorption is not inhibited byendogenous cAMP in the proximal tubule. Additional data shown in Fig. 2 and Table 2 are the effects of both KT-5720 and ANG II on fluidabsorption. Two concentrations of ANG II 10 11 M and10 9 M were examined. J v wassignificantly increased (0.69 ± 0.06 nl/min) when ANG II10 11 M and KT-5720 were added together and was 0.32 ± 0.02 nl · min 1 · mm 1 when ANG II 10 9 M and KT-5720 were added together. Therewere no significant differences between ANG II alone and ANG II plusPKA inhibitor. This result indicates that ANG II stimulatesNa absorption in the proximal tubule by cAMP-independentmechanisms.
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Fig. 2. Effects of PKA inhibitor KT-5720 and ANG II on fluidabsorption in proximal tubules. ANG II 10 11 or10 9 M and KT-5720 (500 nM) were added to the luminalperfusates, respectively.
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Table 2. Effects of PKA inhibitor KT-5720 and ANG II on fluid absorption inproximal tubules
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Effect of TMB-8 and H-7 on PCT fluid absorption. Because stimulation of proximal NHE by PKC has been demonstrated( 25 ), we investigated whether this kinase modulates the effects of ANG II at concentrations that do not alter fluid and Na/HCO 3 − reabsorption. A similar concentration of thecell-permeable PKC inhibitor H-7 was used ( 22 ), and the results of these microperfusion experiments are summarized in Table 3. It should be noted that the additionof either ANG II (10 9 ) or of H-7 alone did not change J v. However, J v decreasedsignificantly when both H-7 and ANG II (10 9 ) were presentin the perfusion solutions. These data suggest that ANG II stimulates J v through PKC activation.

Table 3. Effects of ANG II, TMB-8, and H-7 on fluid absorption in proximaltubules

We further investigated the effects of ANG II by exploring thepossibility that it could inhibit J v byincreasing intracellular Ca 2 . To address this possibility,we assessed the effects of TMB-8 (2 × 10 4 M), ablocker of intracellular calcium mobilization, on fluid absorption.This concentration was similar to that used in previous studies( 23 ). As shown in Table 3, exposure of proximal tubules toTMB-8 alone had no effect on J v, whereasperfusion of proximal tubules with ANG II (10 9 M) andTMB-8 (2 × 10 4 M) resulted in significantstimulation of J v. These findings support thehypothesis that in addition to activation of PKC, ANG II also increasesCa 2  mobilization and produces an inhibition of proximaltubule transport. To further examine this hypothesis, we assessed theeffects of ANG II on J v when both PKC andCa 2  mobilization are blocked. As shown in Fig. 3 and Table 3, the addition of ANG II tothe lumen in the presence of 2 × 10 4 M TMB-8and 10 4 M H-7 did not change J v significantly compared with results obtained in control conditions orin the presence of ANG II (10 9 M) alone. These resultsconfirmed that both PKC and Ca 2  modulate the effects ofANG II.
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Fig. 3. Effects of 3,4,5-trimethoxybenzoicacid-8-(diethylamino)octyl ester (TMB-8),1-(5-isoquinolinesulfonyl)-2-mehtylpiperazine (H-7), and ANG II onfluid absorption in proximal tubules. ANG II (10 9 M),TMB-8 (2 × 10 4 M), and H-7 (10 4 M)were added to the luminal perfusate.
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DISCUSSION

In this study, we first confirmed previous observations that ANGII stimulates Na absorption at a concentration of10 11 M but not at 10 9 M in the proximaltubule ( 21 ). Second, we have shown that inhibition ofendogenous cAMP activity by blocking of PKA did not increase Na absorption. Third, we have demonstrated that ANG II ata concentration of 10 9 M produces stimulation orinhibition of Na transport, depending on whether cytosolicCa 2  mobilization or PKC activity is inhibited. Our dataare consistent with the conclusion that both PKC and cytosolicCa 2  modulate the effects of nanomolar concentration of ANGII. These results also suggested that the luminal effects of ANG II are modulated by second messengers, such as Ca 2  and PKC.Because the physiological concentration of ANG II in tubule fluid iswithin the nanomolar range, the modulation of the effects of ANG II maybe important for regulating absorption of Na in proximaltubules. It should be noted that under our experimental condition, ANGII was only added to the luminal side. It is not clear whether theaddition of different concentrations of ANG II in the bath willmodulate luminal ANG II effects.

Previous studies ( 11, 19, 20 ) in rat and rabbit kidneyshad shown that ANG II has a biphasic effect on Na andHCO 3 − transport in proximal tubules. Severalinvestigations used split-droplet micropuncture procedures and isolatedperfused tubules involving application of ANG II to the capillary byintravenous infusion or added it to the basolateral side of theisolated tubules. In previous experiments, we used in vivo continuousmicroperfusion and applied ANG II directly to the lumen of the proximaltubule. We thus obtained a similar dose response of ANG II on volumeabsorption to that reported previously by Harris and Young( 11 ). Our studies showed that low doses of ANG II(10 12 to 10 11 M) stimulate and high dosesof ANG II (10 8 to 10 5 M) inhibitHCO 3 − transport by modulation of NHE. Maximalstimulation occurs at 10 11 M, whereas maximal inhibitionwas observed at 10 6 M ( 21 ). Similar resultswere also reported by Liu and Cogan ( 14 ) by usingmicroperfusion of early proximal tubule in vivo. With the use of invitro microperfusion of rabbit proximal tubule, it was reported thatthe effects of ANG II differed, depending on the site of application;maximal stimulation resulted from application of 10 11 Min the lumen and 10 10 M induced maximal stimulation onthe basolateral side ( 12 ). However, the effects ofnanomolar concentrations of ANG II in modulating proximal tubuletransport have not been explored.

It was demonstrated ( 5, 26 ) that cAMP inhibits NHE anddecreases Na and HCO 3 − absorption in theproximal tubules. On the basis of observation that ANG II decreasescAMP production and stimulates NHE, it was reported ( 15 )that ANG II stimulates Na and HCO 3 − transport by decreasing cAMP in the proximal tubule. A decrease in cAMPproduction would reduce its inhibitory effect on NHE, resulting inincreased Na and HCO 3 − absorption.However, it is not certain whether NHE activity is inhibited byendogenous cAMP under the physiological conditions. If NHE wereinhibited by endogenous cAMP under basal conditions, inhibition of PKAby KT-5720 would increase NHE activity and increase J v. KT-5720 had no significant effect on J v when it was added to the luminal perfusates,indicating NHE is not inhibited by cAMP under basal conditions. Inaddition, if the stimulatory effect of ANG II on Na transport is due to the reduction of cAMP production, KT-5720 wouldhave a similar incremental effect on J v.However, as shown in Figs. 1 and 2, the addition of ANG II10 11 M and KT-5720 significantly increased J v compared with both control and KT-5720groups. The addition of ANG II 10 9 M and KT-5720 did notchange J v, which was similar to ANG II 10 9 M alone. These results indicate that ANG II modulatesproximal tubule transport independently in cAMP and the PKA signaling pathway.

Experimental data ( 6, 24, 25 ) indicate that bothactivation of PKC and intracellular Ca 2  modulate theproximal tubule transport of Na and HCO 3 − via regulation of the NHE mechanism. Relevant examples include theactivation of PKC resulting in a dose- and time-dependent stimulationof Na and HCO 3 − absorption in ratproximal tubules ( 22 ). PKC also increased NHE activity inbrush-border membrane of rabbit kidneys ( 25 ). Moreover,high concentrations (10 8 to 10 6 M) of ANGII increased cell Ca 2  and reduced Na absorption in rabbit proximal tubule ( 6, 10 ). It has also been shown that ANG II activates the phospholipase C signaling pathway( 27 ); thus increased release of bothinositol-1,4,5,trisphosphate [Ins(1,4,5)IP 3 ]and diacylglycerol elevates cytosolic Ca 2  and active PKC,respectively. Experimental data ( 10, 23 ) show that PKCinhibitors abolish the elevation of fluid and HCO 3 − absorption and Na uptake in microperfused proximal tubulesand cultured proximal tubule cells, respectively. This indicates thatstimulation of proximal tubule transport by ANG II is mediated byactivation of PKC. It was suggested that ANG II acts to stimulate J v by decreasing cAMP ( 15 ), but thedecrease of cAMP is at nanomolar range (EC 50 = 4.4 nM), which is much higher than the stimulation dose of ANG II( 18 ). Therefore, it is uncertain whether the reduction of cAMP by ANG II is the major mechanism of tubule transport stimulation. Our data show ANG II has no effect on J v whenboth PKC and Ca 2  mobilizations were inhibited (Table 3 ),suggesting that a decrease of cAMP by ANG II is not the main mechanismof increased proximal tubule transport. The present studies providestrong evidence supporting the view that stimulatory effects of ANG IIare due to the activation of PKC, because ANG II significantlydecreased the transport after inhibition of PKC. Thus nanomolars of ANG II stimulate PKC activity and upregulate transport. The fact that transport is not affected by 10 9 ANG II alone isconsistent with the documented additional action of ANG II ofincreasing Ca 2  mobilization. The latter inhibitstransport and thus opposes stimulation by PKC.% F% Q5 d, q2 [5 ?3 u

Nanomolar concentrations of ANG II increaseIns(1,4,5)IP 3 (EC 50 = 2.9 nM)and intracellular Ca (EC 50 = 5.5 nM) in the proximal tubule ( 18 ). This suggests that an increase in cellCa 2  is the cellular mechanism of ANG II inhibition.Previous studies ( 10, 23 10 nM increases cell Ca 2  and reduces Na and HCO 3 − absorption and that blocking Ca 2  release from the intracellular pool abolishes theinhibitory effects of ANG II on proximal tubule transport.Nevertheless, this evidence supports the view that ANG II has the dualeffect of activating PKC and increasing intracellular Ca 2 .Our data show that at a dose that does not alter transport, ANG IIeffects stimulation of tubule transport in the presence of TMB-8,indicating that ANG II (10 9 M) increases calciummobilization and decreases proximal tubule transport. Our studies showthat opposite effects, simultaneous stimulation and inhibition oftubule transport by activation of PKC and by increased Ca 2  mobilization, cancel each other, so that ANG II has no net effect on J v. Our results support the view that ANG IIactivation of PKC and increased cell Ca 2  are majormechanisms mediating its biphasic effects on proximal tubuleNa transport.) M+ ]0 K  ~' u3 y: R4 p+ }5 F; u

ACKNOWLEDGEMENTS; o9 D* X) h; e; Z# K( I
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We thank Drs. Gerhard Giebisch, Steven Hebert, and Yuehan Zhou forproviding assistance and constructive comments.
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