Role of PKC and calcium in modulation of effects of angiotensin II on sodium transport in proximal tubule

Zhaopeng Du, William Ferguson, and Tong Wang

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8026


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

It has been well documented that low concentrations of ANG II (10-11 to 10-10 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 ANG II concentration in proximal tubular fluid is in the nanomolar range. In the present study, we investigated the role of PKC, intracellular Ca2+, and cAMP in modulating the effects of luminal ANG II on Na+ absorption by microperfusion techniques in rabbit superficial segment of proximal tubules in vitro. We confirmed that ANG II (10-9 M) had no change on fluid absorption (Jv); however, fluid absorption increased significantly when 10-9 M ANG II and 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester (TMB-8), a blocker of intracellular calcium mobilization, were added together. In contrast, ANG II significantly decreased Jv when PKC was inhibited. When 10-9 M ANG II was present together with 1-(5-isoquinolinesulfonyl)-2-mehtylpiperazine and TMB-8, no significant change of Jv occurred. Inhibition of endogenous cAMP activity by a PKA inhibitor did not change either basal or ANG II-stimulated fluid absorption. Our results indicate that ANG II regulates Na+ absorption by a cAMP-independent mechanism and that PKC and intracellular calcium both play a critical role in modulating the effects of physiological concentration of ANG II on proximal tubule transport. Balance between these two cytosolic messengers modulates the effects of ANG II on fluid absorption in the proximal tubule.

Na+ transport; proximal tubule; microperfusion


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

ANG II IS AN IMPORTANT HORMONAL regulator of Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport in the proximal tubule. ANG II receptors are expressed on both the apical and basolateral side of the proximal tubule (2, 3), and it has been shown to be produced locally and secreted into the tubule fluid (17). ANG II has biphasic effects on Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport in proximal tubules. Low concentrations (10-11 to 10-10 M) stimulate, whereas high concentrations (10-8 to 10-5 M) inhibit Na+ transport in both rats and rabbits (6, 11, 20, 21). Blocking ANG II receptors systemically decreases Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption in proximal tubules of rat kidney (13), which indicates that endogenous ANG II upregulates Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption in the kidney. This is consistent with the reported concentrations of ANG II in the plasma in the picomolar range, which stimulates Na+ absorption (17). In contrast, studies of ANG II concentrations in the proximal tubule fluid have detected levels in the nanomolar range, a concentration 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 cell Ca2+) but high concentrations (10-8 to 10-6 M) of ANG II increase cell Ca2+ and that nanomolar concentrations of ANG II increase PKC activity and intracellular Ca2+ mobilization in the primary cultured rabbit renal proximal tubule cells (10). In the present study, we examined the functional role of cAMP, PKC, and intracellular Ca2+ in modulating the effect of ANG II on Na+ absorption in proximal tubules of rabbit kidney in vitro. Our results show that Na+ transport is not inhibited by endogenous cAMP, whereas both PKC and cytosolic Ca2+ modulate the effects of the nanomolar concentration of ANG II. Dual effects of ANG II of either stimulation or inhibition of transport may be the result of different levels of Ca2+ and PKC activation in proximal tubule cells.


    MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Superficial proximal convoluted tubules (S2 segments) were dissected and perfused in vitro by using conventional methods (9). Briefly, kidneys from adult female New Zealand white rabbits weighing 2-3 kg were removed and cut into coronal slices. Individual tubules were dissected in cooled (4°C) Hanks' solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO4, 0.33 Na2HPO4, 1 MgCl2, 10 Tris · HCl, 0.25 CaCl2, 2 glutamine, and 2 L-lactic acid. The solution was bubbled with 100% O2 and had a pH of 7.4.

S2 segments of the proximal tubules were perfused with an ultrafiltrate-like solution containing (in mM) 125 NaCl, 22 NaHCO3, 1 CaCl2, 1.2 MgSO4, 2 glutamine, 2 lactic acid, 10.5 glucose, 5 KCl, and 1.2 phosphoric acid. A similar solution containing (in mM) 101 NaCl, 22 NaHCO3, 1 CaCl2, 1.2 MgSO4, 2 glutamine, 2 lactic acid, 10.5 glucose, 5 KCl, 1.2 phosphoric acid, and 32.5 HEPES was used as bath medium. Perfusate and bath solutions were bubbled with 95% O2-5% CO2 and had a pH of 7.4. Osmolalities of the bath and perfusate were adjusted to 300 mosmol/kgH2O by the addition of either H2O or NaCl. The bath solution also contained 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. All tubules were perfused at a rate of 10-20 nl/min at 37-38°C in a 1.2-ml temperature-controlled bath. The first period of collection began after an equilibration time of 30-60 min. Net fluid volume absorption (Jv) was measured with [methoxy-3H]inulin. The extensively dialyzed (methoxy-3H)-inulin was added to the perfusate at a concentration of 30 µCi/ml as a volume marker. For each experimental period, three timed collections of tubular fluid were made, the volume of the perfusate and collected samples were measured in a constant-bore glass capillary, and [3H]inulin concentrations in those samples were determined in a liquid scintillation counter (model LS5801; Beckman).

The rate of net fluid reabsorption was calculated according to the following equation: Jv = Vo - VL, where VL is the measured rate of fluid collection and Vo = VL (INL/INo). INL/INo is the ratio of radioactive inulin of collected and original perfusion fluid. The rates of fluid absorption were expressed per millimeter of the proximal tubule.

ANG II was purchased from Peninsula Laboratories (Belmont, CA), and [3H]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 groups with a control group. The difference between the mean values of an experimental group and a control group was considered significant if P < 0.05.


    RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of luminal ANG II on fluid absorption. In the first series of experiments, we confirmed that a low concentration of ANG II stimulates fluid absorption in the S2 segment of the proximal tubule in vitro, as previously observed in the rat in vivo (12, 21). Proximal tubules were microperfused with an ultrafiltrate-like solution containing 125 mM NaCl and 22 mM NaHCO3. Under these conditions, volume reabsorption (Jv) results predominantly from net Na+ absorption.

As shown in Table 1 and Fig. 1, the addition of 10-11 M ANG II to the luminal perfusion solution resulted in significant stimulation of Jv. Jv increased by 127.8%, from 0.36 ± 0.02 to 0.82 ± 0.12 nl · min-1 · mm-1, P < 0.001. In contrast, the addition of 10-9 M ANG II had no effect on fluid absorption. Jv 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 in agreement with previous results that 10-11 M ANG II stimulates Na+ absorption, whereas 10-9 M ANG II 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 (Jv) in proximal tubules. ANG II was added to the luminal perfusate at concentrations of 10-11 and 10-9 M, respectively. Control, without ANG II in the perfusate.

Effect of PKA inhibitor and ANG II on proximal tubule fluid absorption. On the basis of the observation that ANG II decreases cAMP production and stimulates Na+/H+ exchange (NHE), it was reported that ANG II increases the Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> reabsorption rate by inhibition of cAMP, which inhibits NHE (15). It was also demonstrated that ANG II stimulates proximal tubule transport by a cAMP-independent mechanism (4). Although a decrease in cAMP production would reduce its inhibitory effect on NHE, resulting in increased Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption, it is not known whether NHE activity 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 inhibitor KT-5720 at concentrations of 500 nM had no significant effect on Jv 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. This result indicates the net Na+ absorption is not inhibited by endogenous 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 fluid absorption. Two concentrations of ANG II 10-11 M and 10-9 M were examined. Jv was significantly increased (0.69 ± 0.06 nl/min) when ANG II 10-11 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. There were no significant differences between ANG II alone and ANG II plus PKA inhibitor. This result indicates that ANG II stimulates Na+ absorption in the proximal tubule by cAMP-independent mechanisms.


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Fig. 2.   Effects of PKA inhibitor KT-5720 and ANG II on fluid absorption in proximal tubules. ANG II 10-11 or 10-9 M and KT-5720 (500 nM) were added to the luminal perfusates, respectively.


                              
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Table 2.   Effects of PKA inhibitor KT-5720 and ANG II on fluid absorption in proximal tubules

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<UP><SUB>3</SUB><SUP>−</SUP></UP> reabsorption. A similar concentration of the cell-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 addition of either ANG II (10-9) or of H-7 alone did not change Jv. However, Jv decreased significantly when both H-7 and ANG II (10-9) were present in the perfusion solutions. These data suggest that ANG II stimulates Jv through PKC activation.

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

We further investigated the effects of ANG II by exploring the possibility that it could inhibit Jv by increasing intracellular Ca2+. To address this possibility, we assessed the effects of TMB-8 (2 × 10-4M), a blocker 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 to TMB-8 alone had no effect on Jv, whereas perfusion of proximal tubules with ANG II (10-9 M) and TMB-8 (2 × 10-4 M) resulted in significant stimulation of Jv. These findings support the hypothesis that in addition to activation of PKC, ANG II also increases Ca2+ mobilization and produces an inhibition of proximal tubule transport. To further examine this hypothesis, we assessed the effects of ANG II on Jv when both PKC and Ca2+ mobilization are blocked. As shown in Fig. 3 and Table 3, the addition of ANG II to the lumen in the presence of 2 × 10-4 M TMB-8 and 10-4 M H-7 did not change Jv significantly compared with results obtained in control conditions or in the presence of ANG II (10-9 M) alone. These results confirmed that both PKC and Ca2+ modulate the effects of ANG II.


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Fig. 3.   Effects of 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester (TMB-8), 1-(5-isoquinolinesulfonyl)-2-mehtylpiperazine (H-7), and ANG II on fluid 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.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In this study, we first confirmed previous observations that ANG II stimulates Na+ absorption at a concentration of 10-11 M but not at 10-9 M in the proximal tubule (21). Second, we have shown that inhibition of endogenous cAMP activity by blocking of PKA did not increase Na+ absorption. Third, we have demonstrated that ANG II at a concentration of 10-9 M produces stimulation or inhibition of Na+ transport, depending on whether cytosolic Ca2+ mobilization or PKC activity is inhibited. Our data are consistent with the conclusion that both PKC and cytosolic Ca2+ modulate the effects of nanomolar concentration of ANG II. These results also suggested that the luminal effects of ANG II are modulated by second messengers, such as Ca2+ and PKC. Because the physiological concentration of ANG II in tubule fluid is within the nanomolar range, the modulation of the effects of ANG II may be important for regulating absorption of Na+ in proximal tubules. It should be noted that under our experimental condition, ANG II was only added to the luminal side. It is not clear whether the addition of different concentrations of ANG II in the bath will modulate luminal ANG II effects.

Previous studies (11, 19, 20) in rat and rabbit kidneys had shown that ANG II has a biphasic effect on Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport in proximal tubules. Several investigations used split-droplet micropuncture procedures and isolated perfused tubules involving application of ANG II to the capillary by intravenous infusion or added it to the basolateral side of the isolated tubules. In previous experiments, we used in vivo continuous microperfusion and applied ANG II directly to the lumen of the proximal tubule. We thus obtained a similar dose response of ANG II on volume absorption 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 doses of ANG II (10-8 to 10-5 M) inhibit HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport by modulation of NHE. Maximal stimulation occurs at 10-11 M, whereas maximal inhibition was observed at 10-6 M (21). Similar results were also reported by Liu and Cogan (14) by using microperfusion of early proximal tubule in vivo. With the use of in vitro microperfusion of rabbit proximal tubule, it was reported that the effects of ANG II differed, depending on the site of application; maximal stimulation resulted from application of 10-11 M in the lumen and 10-10 M induced maximal stimulation on the basolateral side (12). However, the effects of nanomolar concentrations of ANG II in modulating proximal tubule transport have not been explored.

It was demonstrated (5, 26) that cAMP inhibits NHE and decreases Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption in the proximal tubules. On the basis of observation that ANG II decreases cAMP production and stimulates NHE, it was reported (15) that ANG II stimulates Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> transport by decreasing cAMP in the proximal tubule. A decrease in cAMP production would reduce its inhibitory effect on NHE, resulting in increased Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption. However, it is not certain whether NHE activity is inhibited by endogenous cAMP under the physiological conditions. If NHE were inhibited by endogenous cAMP under basal conditions, inhibition of PKA by KT-5720 would increase NHE activity and increase Jv. KT-5720 had no significant effect on Jv when it was added to the luminal perfusates, indicating NHE is not inhibited by cAMP under basal conditions. In addition, if the stimulatory effect of ANG II on Na+ transport is due to the reduction of cAMP production, KT-5720 would have a similar incremental effect on Jv. However, as shown in Figs. 1 and 2, the addition of ANG II 10-11 M and KT-5720 significantly increased Jv compared with both control and KT-5720 groups. The addition of ANG II 10-9 M and KT-5720 did not change Jv, which was similar to ANG II 10-9 M alone. These results indicate that ANG II modulates proximal tubule transport independently in cAMP and the PKA signaling pathway.

Experimental data (6, 24, 25) indicate that both activation of PKC and intracellular Ca2+ modulate the proximal tubule transport of Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> via regulation of the NHE mechanism. Relevant examples include the activation of PKC resulting in a dose- and time-dependent stimulation of Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption in rat proximal tubules (22). PKC also increased NHE activity in brush-border membrane of rabbit kidneys (25). Moreover, high concentrations (10-8 to 10-6 M) of ANG II increased cell Ca2+ 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 both inositol-1,4,5,trisphosphate [Ins(1,4,5)IP3] and diacylglycerol elevates cytosolic Ca2+ and active PKC, respectively. Experimental data (10, 23) show that PKC inhibitors abolish the elevation of fluid and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption and Na+ uptake in microperfused proximal tubules and cultured proximal tubule cells, respectively. This indicates that stimulation of proximal tubule transport by ANG II is mediated by activation of PKC. It was suggested that ANG II acts to stimulate Jv by decreasing cAMP (15), but the decrease of cAMP is at nanomolar range (EC50 = 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 Jv when both PKC and Ca2+ mobilizations were inhibited (Table 3), suggesting that a decrease of cAMP by ANG II is not the main mechanism of increased proximal tubule transport. The present studies provide strong evidence supporting the view that stimulatory effects of ANG II are due to the activation of PKC, because ANG II significantly decreased 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 is consistent with the documented additional action of ANG II of increasing Ca2+ mobilization. The latter inhibits transport and thus opposes stimulation by PKC.

Nanomolar concentrations of ANG II increase Ins(1,4,5)IP3 (EC50 = 2.9 nM) and intracellular Ca (EC50 = 5.5 nM) in the proximal tubule (18). This suggests that an increase in cell Ca2+ is the cellular mechanism of ANG II inhibition. Previous studies (10, 23) have also demonstrated that ANG II >10 nM increases cell Ca2+ and reduces Na+ and HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> absorption and that blocking Ca2+ release from the intracellular pool abolishes the inhibitory effects of ANG II on proximal tubule transport. Nevertheless, this evidence supports the view that ANG II has the dual effect of activating PKC and increasing intracellular Ca2+. Our data show that at a dose that does not alter transport, ANG II effects stimulation of tubule transport in the presence of TMB-8, indicating that ANG II (10-9 M) increases calcium mobilization and decreases proximal tubule transport. Our studies show that opposite effects, simultaneous stimulation and inhibition of tubule transport by activation of PKC and by increased Ca2+ mobilization, cancel each other, so that ANG II has no net effect on Jv. Our results support the view that ANG II activation of PKC and increased cell Ca2+ are major mechanisms mediating its biphasic effects on proximal tubule Na+ transport.


    ACKNOWLEDGEMENTS

We thank Drs. Gerhard Giebisch, Steven Hebert, and Yuehan Zhou for providing assistance and constructive comments.


    FOOTNOTES

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-17433.

Portions of this study were previously published in abstract form (7).

Address for reprint requests and other correspondence: T. Wang, Dept. of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar St., P.O. Box 208026, New Haven, CT 06520-8026 (E-mail: tong.wang{at}yale.edu).

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.

First published January 14, 2003;10.1152/ajprenal.00261.2002

Received 19 July 2002; accepted in final form 6 December 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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