Published online before print September 30, 2002, doi: 10.1161/01.HYP.0000036449.70110.DE
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(Hypertension. 2002;40:707.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Biphasic Regulation of Na+-HCO3- Cotransporter by Angiotensin II Type 1A Receptor
From the Department of Internal Medicine, Faculty of Medicine, Tokyo University (S.H., Y.Z., C.H., H.Y., M.K., S.T., S.U., A.G., T.F., G.S.), Tokyo; and Discovery Research Laboratory, Tanabe Seiyaku Co Ltd (T.S.), Osaka, Japan.
Correspondence to George Seki, MD, Department of Internal Medicine, Faculty of Medicine, Tokyo University, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail georgeseki-tky{at}umin.ac.jp
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Abstract |
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Although angiotensin (Ang) II is known to regulate renal proximal transport in a biphasic way, the receptor subtype(s) mediating these Ang II effects remained to be established. To clarify this issue, we compared the effects of Ang II in wild-type mice (WT) and Ang II type 1A receptor–deficient mice (AT1A KO). The Na+-HCO3- cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with a fluorescent probe, was stimulated by 10-10 mol/L Ang II but was inhibited by 10-6 mol/L Ang II in WT. Although valsartan (AT1 antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT2 antagonist) did not modify these effects of Ang II. In AT1A KO, in contrast, this biphasic regulation was lost, and only stimulation of NBC activity by 10-6 mol/L Ang II was observed. This stimulation was blocked by valsartan but not by PD 123,319. More than 10-8 mol/L Ang II induced a transient increase in cell Ca2+ concentrations in WT, which was again blocked by valsartan but not by PD 123,319. However, up to 10-5 mol/L Ang II did not increase cell Ca2+ concentrations in AT1A KO. Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT1A KO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT1A KO. These results indicate that AT1A mediates the biphasic regulation of NBC. Although low-level expression of AT1B could be responsible for the stimulation by 10-6 mol/L Ang II in AT1A KO, no evidence was obtained for AT2 involvement.
Key Words: receptors, angiotensin II • renal circulation • sodium • arachidonic acids
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Introduction |
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Angiotensin (Ang) II receptors can be pharmacologically divided into 2 major subtypes, type 1 (AT1) and type 2 (AT2) receptors, and AT1 receptors are further divided into AT1A and AT1B receptors.1,2 In the kidney, the expression of AT1A is shown to be far more abundant than that of AT1B.3–6 Although the physiological effects of Ang II are generally thought to be mediated by AT1 receptors,1,2 recent studies suggest that AT2 may also be involved in the regulation of cardiovascular system.7
In addition to the influence on renal hemodynamics, Ang II exerts direct effects on renal tubular functions. For example, Ang II acts primarily on Na+ and HCO3- reabsorption in proximal tubules, and this process is considered to play quite an important role in the regulation of body fluid and sodium balance.8–11 Interestingly, it has been reported that Ang II regulates renal proximal transport in a biphasic way; low (picomolar to nanomolar) concentrations of Ang II cause stimulation, whereas high (nanomolar to micromolar) concentrations of Ang II cause inhibition.8,9 Although several studies12,13 support a view that AT1 mediates both stimulatory and inhibitory effects of Ang II, Haithcock et al14 presented the evidence that AT2 mediates the inhibitory effect of Ang II. Methodological differences may not fully account for these controversial results, and the definite conclusion as to the receptor subtype(s) mediating the biphasic regulation of proximal transport remains to be established. This issue would be quite important, not only for the understanding of Ang II–signaling pathways but also for the clinical point of view, because AT1 antagonists are now widely used in a variety of clinical situations. In the present study, we therefore compared the effects of Ang II in isolated nonperfused proximal tubules from wild-type mice (WT) and AT1A knockout mice (KO).15 Because the Na+-HCO3- cotransporter (NBC) is responsible for a majority of bicarbonate uptake from proximal tubules in this experimental condition and is one of the target transporters of Ang II,16–22 we focused on the regulation of NBC by Ang II.
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Methods |
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Animals
Male AT1A KO mice and WT mice (Discovery Research Laboratory, Tanabe Seiyaku Co Ltd, Osaka, Japan), 5 to 8 weeks old, from the same genetic background (C57B6) were used in the present study.15 They were provided with standard food and water at libitum. All animal procedures were in accordance with local institutional guidelines.
Measurements of NBC Activity
NBC activity was determined as previously described.17,22 In brief, mice were anesthetized with pentobarbital sodium, and thin sections from the left kidney were obtained. Proximal tubules (S2 segment) were microdissected from mice without collagenase treatment. The tubule fragment was transferred to a perfusion chamber mounted on an inverted microscopy, and both ends of tubule were sucked into 2 holding pipettes. To avoid the influence of luminal transporters, the luminally collapsed tubule was used. The tubule was incubated with an acetoxymethylester form of a pH-sensitive fluorescence dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF/AM) for 10 minutes, and intracellular pH (pHi) was monitored with a photometry system (OSP-10, Olympus). Dulbecco’s modified Eagle’s medium (DMEM) was used for the bath perfusate, and 10 µmol/L norepinephrine was added to improve the functions of isolated proximal tubules as described.22–24
Our preliminary experiments indicated that bicarbonate reabsorption rates from isolated microperfused mouse proximal tubules were preserved at high levels for up to 60 minutes in DMEM solution containing norepinephrine, but were deteriorated within 60 minutes in Ringer solution. The chamber was perfused at a rate of 10 mL/min with the prewarmed (38°C) perfusate that was equilibrated with 5% CO2/95% O2 gas. During the experiments, bath HCO3- concentrations were repeatedly reduced from 25 to 12.5 mmol/L. Previous studies on isolated rabbit and rat proximal tubules have shown that the pHi response by bath HCO3- reduction in this condition is mediated by the basolateral Na+-HCO3- cotransporter, NBC.16,17,22 This is based on the observations that the pHi response by bath HCO3- reduction was insensitive to basolateral addition of amiloride, an inhibitor of Na+/H+ exchanger, or to bath Cl- removal but was largely suppressed by 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of NBC. Our preliminary experiments confirmed that the pHi response in mouse proximal tubules was also insensitive to amiloride but was largely inhibited by DIDS. The intracellular buffer capacity was determined by sudden changes of bath CO2 tension as described,16,17,22 and the pHi calibration curves were obtained according to the method by Thomas et al.25
Measurements of [Ca2+]i Concentrations
[Ca2+]i was measured as previously described,17 but the method of Fura-2 loading was slightly modified. Briefly, the tubules were incubated with 30 µmol/L Fura-2/AM for 60 minutes in DMEM under 5% CO2/95% O2 gas at 37°C. Thereafter, the tubule was transferred into the perfusion chamber, and [Ca2+]i was monitored with the OSP-10 system. The calibration curves were obtained at the end of each experiment, and [Ca2+]i was calculated according to the method by Grynkiewicz et al.26
Materials and Statistics
BCECF/AM and Fura-2/AM were obtained from Dojindo; valsartan was from Novartis; 5-ile-Ang II, PD 123,319, arachidonic acid, phorbol 12-myristate 13-acetate (PMA), and nigericin were from Sigma. All the other chemicals were from Wako. The data were represented as mean±SEM. Significant differences were determined by applying the paired or unpaired Student t test as appropriate.
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Results |
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Effects of Ang II on NBC in WT
We first examined the effects of 10-10, 10-8, and 10-6 mol/L Ang II in isolated proximal tubules from WT. Although bath addition of 10-10 and 10-8 mol/L Ang II did not change the steady state pHi, the addition of 10-6 mol/L Ang II slightly increased pHi by 0.03±0.003 pH unit(n=7; P<0.01). Time control experiments without Ang II confirmed that the rates of pHi decrease did not change in response to repeated bath HCO3- reduction (1.30±0.06 versus 1.31±0.07 pH unit/min, n=5; P=NS). However, 5-minute incubation with 10-10 mol/L Ang II significantly increased the rates of pHi changes in response to bath HCO3- reduction by 28 ±2% (n=7; P<0.005). On the other hand, 10-8 mol/L Ang II had no effects (n=7), and 10-6 mol/L Ang II rather decreased the rates of pHi changes by 28±4% (n=7; P<0.005). In separate tubules, the cell buffer capacity (68.7±2.6 mmol/L pH unit, n=14) was confirmed to be unaffected by these concentrations of Ang II, and the HCO3- fluxes calculated from the initial rates of pHi decrease and the cell buffer capacity were shown in Figure 1. As can be seen, Ang II has the biphasic effects on NBC activity in mice as previously shown in rabbits.19,20
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To examine the receptor subtype(s) mediating these responses to Ang II, we tested an AT1 antagonist valsartan. The addition of 2x10-7 mol/L valsartan alone did not affect the rates of pHi changes to bath HCO3- reduction (n=6), but completely blocked both stimulation and inhibition by Ang II. Thus, in the presence of valsartan, the rates of pHi changes to bath HCO3- reduction were not changed by 10-10 mol/L Ang II (1.43±0.06 versus 1.41±0.09 pH unit/min, n=7; P=NS) and by 10-6 mol/L Ang II (1.36±0.10 versus 1.38±0.10 pH unit/min, n=7; P=NS). Valsartan also completely blocked the increase in steady state pHi by 10-6 mol/L Ang II (n=7).
Because some investigators have reported that the inhibition by high concentrations of Ang II is mediated by AT2,14 we also tested an AT2 antagonist PD 123,319. The addition of 10-5 mol/L PD 123,319 alone did not change the rates of pHi decrease to bath HCO3- reduction, and 10-10 mol/L Ang II increased the rates of pHi changes from 1.29±0.04 to 1.67±0.09 pH unit/min (n=6; P<0.005) in the presence of PD 123,319. Furthermore, 10-6 mol/L Ang II still decreased the rates of pHi changes from 1.33±0.07 to 0.99±0.07 pH unit/min (n=6; P<0.005) in the presence of PD 123,319. These results are consistent with a view that both stimulatory and inhibitory effects of Ang II are mediated by AT1.
Effects of Ang II on NBC in AT1A KO
We next examined the effects of Ang II in AT1A KO. Time control experiments without Ang II confirmed that the rates of pHi decrease did not change in response to repeated bath HCO3- reduction (1.35±0.07 versus 1.33±0.06 pH unit/min, n=5; P=NS), and 10-10 and 10-8 mol/L Ang II did not affect the rates of pHi changes to bath HCO3- reduction. On the other hand, 10-6 Ang II increased the rates of pHi changes by 18±2% (n=7; P<0.005). The cell buffer capacity (67.0±2.8 mmol/L pH unit, n=13) was not affected by these concentrations of Ang II, and the calculated HCO3- fluxes are shown in Figure 2. As can be seen, 10-6 mol/L Ang II indeed stimulated the NBC activity in AT1A KO, whereas other concentrations of Ang II had no effects. To determine the receptor subtype mediating the Ang II effect in AT1A KO, we again applied valsartan and PD 123,319. Neither valsartan nor PD 123,319 changed the rates of pHi decrease to bath HCO3- reduction. In the presence of valsartan, the stimulation by 10-6 mol/L Ang II was completely abolished (1.39±0.1 versus 1.36±0.07 pH unit/min, n=7; P=NS). On the other hand, 10-6 mol/L Ang II still increased the rates of pHi changes to bath HCO3- reduction from 1.22±0.06 to 1.49±0.04 pH unit/min (n=6; P<0.005) in the presence of 10-5 mol/L PD 123,319. These results suggest that the stimulation by 10-6 mol/L Ang II in AT1A KO may be mediated by AT1B.
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Effects of Ang II on [Ca2+]i in WT and AT1A KO
Because the changes in [Ca2+]i could be an important factor in the regulation of renal proximal transport by Ang II,12,13,27,28 we next examined the [Ca2+]i responses to Ang II. In WT, the addition of 10-8 and 10-6 mol/L Ang II induced a transient spikelike increase in [Ca2+]i, as shown in Figure 3. In all 6 tested tubules, 10-8 and 10-6 mol/L Ang II induced the very similar spikelike responses. On the other hand, 10-10 Ang II did not induce a spikelike increase in [Ca2+]i. In 3 tubules, 10-10 Ang II induced a marginal increase in [Ca2+]i, as shown in Figure 3, but [Ca2+]i was not increased at all in the remaining 3 tubules. To examine the receptor subtypes involved in these [Ca2+]i responses, we again tested valsartan. Sequential additions of 10-6 mol/L Ang II in the same tubule, separated for >3 minutes, elicited comparable [Ca2+]i increases (n=5). To determine the influence of valsartan, we therefore applied 10-6 mol/L Ang II twice in the same tubule, first in the absence of valsartan and second in the presence of valsartan. The concentration dependence of valsartan effects thus determined is shown in Figure 4. As can be seen, valsartan was quite effective in blocking the [Ca2+]i increase by 10-6 mol/L Ang II, and percent inhibition by 2x10-7 mol/L valsartan was 91±5% (n=6). By contrast, 10-5 mol/L PD 123,319 failed to affect the [Ca2+]i responses to 10-6 mol/L Ang II (n=5), indicating that AT1 mediates the [Ca2+]i increase in WT.
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We also examined the effects of up to 10-5 mol/L Ang II on [Ca2+]i in AT1A KO. However, we could not detect any [Ca2+]i increase in AT1A KO.
Effects of Arachidonic Acid and PMA on NBC
High concentrations of Ang II are known to activate phospholipase A2 (PLA2), and the subsequent arachidonic acid release is thought be responsible for the inhibition by high concentrations of Ang II.13,29,30 We therefore compared the effects of arachidonic acid on NBC-1 activity in WT and AT1A KO. The addition of 10-8 mol/L arachidonic acid slightly increased the steady-state pHi in both WT (0.027±0.004 pH unit, n=6; P<0.005) and AT1A KO (0.029±0.005, n=6; P<0.005) without changing cell buffer capacity. As shown in Figure 5, the calculated HCO3- fluxes in response to bath HCO3- reduction were similarly decreased by arachidonic acid in both WT (-20±2%, n=6) and AT1A KO (-21±2%, n =6). These results indicate that WT and AT1A KO have the similar responsiveness to arachidonic acid.
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Because the acute activation of PKC was shown to stimulate the NBC activity,17 we also tested PMA, an activator of PKC. The addition of 5x10-7 mol/L PMA for 5 minutes similarly increased the HCO3- fluxes in response to bath HCO3- reduction in both WT (30±4%, n=6) and AT1A KO (29±4%, n =6).
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Discussion |
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Renal proximal tubules reabsorb a majority of filtered sodium and bicarbonate. This process is mediated by the coordinated operation of the apical Na+-H+ exchanger and the basolateral Na+-HCO3- cotransporter, whereas the electrochemical driving forces required for this process to work is provided by the basolateral Na+-K+ ATPase. Among these transporters, the physiological importance of Na+-HCO3- cotransporter, most likely encoded by NBC-1,31 is highlighted by our recent finding that inactivating mutations in NBC-1 cause proximal renal tubular acidosis with ocular abnormalities.32,33 Although several hormones have been shown to affect the transport process in this segment, the biphasic effects of Ang II on volume and bicarbonate reabsorption from proximal tubules have been consistently confirmed.8,9,27 Subsequent studies have clarified that activities of the apical Na+-H+ exchanger, the basolateral Na+-HCO3- cotransporter, and Na+-K+ ATPase are regulated by Ang II in the biphasic way.13,19,20,30,34 The signal transduction pathways have been also clarified. Thus, the stimulation by low concentrations of Ang II is thought to be mediated by the decrease in the level of cAMP in the cell and/or by the activation of protein kinase C.11,21,35
A recent study suggests that tyrosine kinases may be also involved in the stimulation by Ang II.36 On the other hand, the inhibition by high concentrations of Ang II is thought to involve the activation of PLA2 and the subsequent release of arachidonic acid. The arachidonic acid would be then metabolized via cytochrome P450-dependent epoxygenase pathway, and a resultant metabolite, 5,6-epoxyeicosatrienoic acid, could be a mediator of the inhibition by Ang II.13,29,30 Although it has been generally accepted that AT1 mediates the stimulation by low concentrations of Ang II, the controversial results have been reported as to the receptor subtype mediating the inhibition by high concentrations of Ang II.12–14,30 To clarify this issue, we took advantage of genetically engineered mice. The AT1A KO used in the present study showed lowered blood pressure despite the presence of hyperreninemia.15 Although their AT1A gene is completely disrupted, AT1A KO are known to express AT1B.37
The present study was performed on lumen-collapsed tubules, in which Na+ and HCO3- ions are expected to approach the equilibrium distribution across the basolateral membrane, and the basolateral cell membrane potentials should then approach the reversal potential of the major basolateral electrogenic transporter NBC.16 In addition, we confirmed that not only the initial rates of pHi decrease but also HCO3- fluxes induced by sudden reduction of bath HCO3- concentrations were indeed altered by Ang II. These considerations and observations strongly suggest that Ang II directly regulates the NBC activity, although future studies would be required to clarify a role of Ang II–induced changes in K+ conductance,19,20 which might indirectly affect the NBC activity.
Our results showed that the NBC activity was stimulated by 10-10 Ang II but was inhibited by 10-6 Ang II in WT. In AT1A KO, this type of biphasic regulation was lost, and only stimulation by 10-6 Ang II was observed. The highly selective AT1 antagonist valsartan38 blocked both stimulation and inhibition by Ang II in WT, and also blocked the stimulation by Ang II in AT1A KO. On the other hand, the AT2 antagonist PD 123,319 did not modify the effects of 10-6 Ang II in both WT and AT1A KO. From these observations, we can conclude that the biphasic regulation of NBC by Ang II is mediated by the basolateral AT1A. An in situ hybridization study has confirmed the low-level expression of AT1B in proximal tubules.4 It has been also reported that the inhibitory effects of valsartan on AT1A and AT1B are indistinguishable.39,40 Therefore, the stimulation by 10-6 Ang II in AT1A KO seems to be most likely mediated by the basolateral AT1B, although we cannot completely exclude a possibility that high concentrations of Ang II might result in some of the peptide diffusing into the apical surface of the collapsed tubules and act also on the apical receptor. The physiological significance of AT1B in proximal tubules is not clear at present. However, unlike AT1A KO, AT1A/AT1B double knockout mice exhibited gross morphological abnormality in the kidney,41 suggesting that AT1B in the kidney may have some physiological roles in vivo. We could not obtain AT1B-deficient mice, but the future experiments on isolated tubules from these mice would help clarify this issue.
In the present study, >10-8 mol/L Ang II was necessary to induce the typical spikelike [Ca2+]i increase in WT. In contrast, others42 have reported that isolated rat proximal tubules were able to respond to much lower concentrations of Ang II. The reason for these discrepant results is not apparent at present, but the species difference or the different metabolic status of isolated tubules could be responsible. We observed that the [Ca2+]i response in WT was again inhibited by valsartan but not by PD 123,319. The dose-response curve of the inhibitory effects of valsartan on Ang-II–induced [Ca2+]i increase was almost identical with that determined on the rat vascular AT1 receptors.38 In AT1A KO, however, up to 10-5 mol/L Ang II failed to increase [Ca2+]i. These results indicate that the [Ca2+]i increase in WT is mediated by AT1A. They also suggest that the substantial increase in [Ca2+]i may augment the inhibitory effects of Ang II. Consistent with this view, the [Ca2+]i increase by high concentrations of Ang II has been reported to activate PLA2, facilitating the arachidonic acid release.13 On the other hand, the pharmacological properties of AT1A and AT1B are known to be very similar.1,2 In addition, the exogenous arachidonic acid inhibited the NBC-1 activity similarly in WT and AT1A KO. Therefore, it might be reasonable to speculate that the low-level expression of AT1B could be sufficient to mediate the stimulation by Ang II in AT1A KO but might be insufficient to induce the significant [Ca2+]i increase. At present, the question as to why the AT1A receptor in renal proximal tubules, unlike that in other tissues, mediates the biphasic effects is rather difficult to answer. However, it is interesting to note that the cytochrome P450 activity in the kidney is primarily localized in proximal tubules.43
In contrast to our conclusion, Haithcock and colleagues14 have presented the evidence that AT2 mediates the inhibition by Ang II. They used cultured proximal tubular cells that might express the apical Ang II receptors, whereas our study was limited on the basolateral receptors in intact proximal tubules. This methodological difference alone, however, may not explain the controversial results, because Han and colleagues,13 using the similar cultured tubular cells, have concluded that AT1 mediates both stimulation and inhibition. Although the reason for the discrepant results remains still unclear, the AT2 expression is generally considered to be very low or undetectable in both the cortex and medulla of adult mammalian kidneys.44
Perspectives
We demonstrated, for the first time to our knowledge, that the basolateral AT1A mediates both stimulation and inhibition of NBC by Ang II. Although we could not obtain evidence for a role of AT2, the receptor subtype(s) mediating luminal Ang II actions should be defined in the future studies.
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Acknowledgments |
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This study was in part supported by grant 14571013 from the Ministry of Education, Science and Culture of Japan.
Received June 19, 2002; first decision July 9, 2002; accepted August 26, 2002.
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