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Departments of Medicine and Physiology, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama
The Water and Salt Research Center and Institute of Anatomy, University of Aarhus, Aarhus C, Denmark
Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary
Department of Physiology and Biophysics and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California
ABSTRACT
Functional and immunohistological studies were performed to identify basolateral chloride/bicarbonate exchange in macula densa cells. Using the isolated, perfused thick ascending limb with attached glomerulus preparation dissected from rabbit kidney, macula densa intracellular pH (pHi) was measured with fluorescence microscopy and BCECF. For these experiments, basolateral chloride was reduced, resulting in reversible macula densa cell alkalinization. Anion exchange activity was assessed by measuring the maximal net base efflux on readdition of bath chloride. Anion exchange activity required the presence of bicarbonate, was independent of changes in membrane potential, did not require the presence of sodium, and was inhibited by high concentrations of DIDS. Inhibition of macula densa anion exchange activity by basolateral DIDS increased luminal NaCl concentration-induced elevations in pHi. Immunohistochemical studies using antibodies against AE2 demonstrated expression of AE2 along the basolateral membrane of macula densa cells of rabbit kidney. These results suggest that macula densa cells functionally and immunologically express a chloride/bicarbonate exchanger at the basolateral membrane. This transporter likely participates in the regulation of pHi and might be involved in macula densa signaling.
chloride/bicarbonate antiporters; acid-base equilibrium; juxtaglomerular apparatus; sodium/hydrogen antiporters
THE MACULA DENSA IS A PLAQUE of specialized epithelial cells located at the site where the distal nephron returns to the vascular pole of its own glomerulus. These cells are considered to be a "sensory window" that detects changes in the tubular environment and transmits signals to the vascular elements. This pathway provides the structural basis for macula densa-mediated tubuloglomerular feedback and the release of renin from granular cells. Elevations in luminal sodium chloride concentration (L) lead to sodium entry through the apical furosemide-sensitive sodium-potassium-chloride symporter (NKCC2) and the sodium/hydrogen antiporter (NHE2). As the result of sodium/hydrogen antiport activity, elevations in L alkalinize macula densa cells (9). Furthermore, alterations in L cause changes in membrane potential, cell volume, and cytosolic concentrations of Na+, Cl, and Ca2+; some or all of these changes in macula cell function may serve in macula densa cell signaling. To date, it has been established that macula densa cells signal through the release of ATP, prostaglandin E2, and nitric oxide (3, 15, 21). However, the linkage between the cellular responses that occur in macula densa cells with changes in L and the release of paracrine factors by macula densa cells is poorly understood. Also, the mechanisms that lead to changes in L-dependent macula cell function are not well understood. This is particularly true concerning the regulation of intracellular pH (pHi) in macula densa cells. This is important as recent work has suggested that cell pH may be involved in the regulation of nitric oxide release by macula densa cells (15, 30). Although sodium/hydrogen antiporters have been identified at both apical and basolateral membranes of macula densa cells, it is also possible that other acid-base transport systems could be involved in the regulation of macula densa cell pH. One potential transport pathway that may be involved in pH regulation is chloride/bicarbonate anion exchange.
To date, 10 members of the SLC4 bicarbonate transporter gene family have been reported of which three isoforms (SLCA13 or AE13) have been unequivocally shown to mediate sodium-independent chloride/bicarbonate antiport activity (1, 23). AE4 is suggested to be responsible for sodium-bicarbonate cotransport (23). A splice variant of AE1, AE3, and AE4 isoforms is all expressed in the kidney; however, none of these isoforms have been observed in the cortical thick ascending limb (cTAL) or macula densa (6, 12, 14). In contrast, the constitutive isoform, AE2, is present in nearly all rodent nephron segments with robust expression having been observed at the macula densa basolateral membrane (2, 5, 29). In a recent study, expression of a NH2-terminal variant, AE2b, has also been described in rat macula densa, and this isoform is upregulated by chronic acid loading (10). A second distinct family of bicarbonate transporters (SLC26), capable of chloride/bicarbonate antiport activity, has recently been delineated, purportedly playing a role in the acid-base transport by the collecting duct (19, 22).
Sodium-independent chloride/bicarbonate antiporters translocate monovalent anions across plasma membranes via electroneutral exchange. Because the inward chloride gradient is almost always larger than the inward bicarbonate gradient, chloride uptake in exchange for bicarbonate efflux represents "physiological" anion exchange. It is reasonable to postulate that chloride/bicarbonate antiport contributes to the regulation of pHi by exporting bicarbonate in response to intracellular alkali loads. In this regard, the activity of AE2 is stimulated by increases in pHi (28). In addition, AE2 may also play a role in the regulation of cell volume by contributing to volume-regulatory increases with cellular uptake of chloride. The present study was designed to characterize chloride/bicarbonate exchange in macula densa cells and to determine if it plays a role in macula densa pHi regulation.
METHODS
Materials. All materials were purchased from Sigma (St. Louis, MO) unless otherwise stated. BCECF/AM was obtained from Teflabs (Austin, TX). DIDS was freshly dissolved in warm solutions and used within 2 h.
Tubule perfusion. Individual cTALs containing the macula densa segment with attached glomeruli were dissected from rabbit kidneys (New Zealand White rabbits; 0.51.0 kg; Myrtle's Rabbitry, Thompson Station, TN; n = 35 animals total) and perfused in vitro using methods similar to those described previously (15, 20). Dissection was performed at 4°C in an isosmotic, low-NaCl-containing Ringer ("dissection") solution (Table 1). After transfer to a chamber that was mounted on the microscope, the tubule was cannulated and perfused with "perfusion" solution (Table 1). Tubules were initially bathed in "bath high-chloride" solution. Nominally bicarbonate-free solutions were achieved by bubbling with 100% O2, instead of 5% CO2-95% O2; high-K+ solutions were prepared by isosmotically replacing NMDG with K+. All experiments were conducted at 37°C.
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Fluorescence microscopy. Macula densa cells were loaded with BCECF by adding BCECF/AM (105 mol/l) dissolved in dimethyl sulfoxide to the luminal perfusate. Loading required 5 min. pHi was measured in BCECF-loaded macula densa cells with dual-excitation wavelength fluorescence microscopy (PTI, Lawrenceville, NJ) using a Nikon S Fluor x40 objective and a cooled SenSys charge-coupled camera (Photometrics, Tucson, AZ). Fluorescence was measured at an emission wavelength of 530 nm in response to excitation wavelengths of 495 and 440 nm, alternated by a computer-controlled chopper assembly. The autofluorescence-corrected 495/440 ratios were converted into pHi values using the nigericin/high-K+ calibration technique. Chloride/bicarbonate exchange activity was assessed by monitoring chloride-dependent pHi recovery from an acid load imposed by chloride removal. Measurements consisted of assessing the initial rate of pHi recovery (pHi/t, calculated from a linear fit, PTI software) and the magnitude of change in pHi in response to alterations in basolateral chloride concentration ([Cl]B). Net base flux Jbase was determined according to Eq. 1, where actual intrinsic buffering capacity (int) was calculated using its published relationship to MD pHi (16). BCO2 was calculated as 2.3 x [HCO3]i, where [HCO3]i is the intracellular bicarbonate concentration obtained using the Henderson-Hasselbalch equation (4).
(1)
Antibodies anti-AE2a/b ( 101117). Studies were performed using an affinity-purified rabbit polyclonal antibody raised against a synthetic peptide identical to amino acids 101117 of rat AE2a recognizing mouse and rat AE2a and AE2b isoforms (10). The splicing pattern of the rabbit AE2 gene resembles the rat AE2 gene, and rabbit AE2a amino acids 101117 are identical, except for the last residue, to the rat sequence (7, 24).
Immunohistochemistry of rabbit kidney sections. Kidneys from a rabbit were fixed by retrograde perfusion with 4% paraformaldehyde in 0.1 mol/l cacodylate buffer (pH 7.4) and subsequently postfixed for 1 h in similar fixative. Kidney sections were dehydrated, embedded in paraffin, and cut in 2-μm-thick slices on a rotary microtome (Leica). Sections were then dewaxed in xylene and rehydrated from 99% ethanol to 96% ethanol. At this hydration level, endogenous peroxidase activity was blocked by incubation for 30 min in 0.3% H2O2 in methanol. Rehydration was completed from 96 to 70% ethanol. Sections were then placed in 10 mmol/l Tris buffer (pH 9.0) containing 0.5 mmol/l EGTA (Titriplex VI, Merck) and heated in a microwave oven for 10 min. Nonspecific binding of immunoglobulin was prevented by incubating sections in 50 mmol/l NH4Cl for 30 min followed by blocking in PBS supplemented with 1% BSA, 0.05% saponin, and 0.2% gelatin. Sections were incubated overnight at 4°C with affinity-purified anti-AE2a/b ( 101117) antibodies diluted 1:8,000 in 10 mmol/l PBS (pH 7.4) containing 0.3% Triton X-100 and 0.1% BSA. After incubation in the primary antibody, sections were washed in PBS supplemented with 0.1% BSA, 0.05% saponin, and 0.2% gelatin and incubated for 1 h at room temperature with horseradish peroxidase-linked goat anti-rabbit secondary antibodies (P448, DAKO, Glostrup, Denmark) diluted 1:200 in PBS (pH 7.4) containing 0.3% Triton X-100 and 0.1% BSA. Labeling was visualized by incubation for 10 min with 1 mg/ml DAB (cat. no. 4170, Kem-En-Tec Diagnostics, Copenhagen, Denmark) in water supplemented with 0.03% H2O2 just before use. After 3 x 10-min washes in PBS (pH 7.4), sections were briefly rinsed in distilled water and counterstained with Mayers hematoxylin and washed in tap water before dehydration and mounting.
Statistical analyses. Data are expressed as means ± SE. Statistical significance was tested using an unpaired t-test or ANOVA. P < 0.05 was considered significant.
RESULTS
Identification of macula densa basolateral chloride/bicarbonate antiport. In the absence of basolateral Na+ and at a [Cl]B of 133 mmol/l and [HCO3]B of 27 mmol/l ["bath high-chloride" solution (Table 1)] and with 25 mmol/l of Na+ in the luminal perfusate ("Perfusion" solution), macula densa pHi averaged 6.95 ± 0.03 (n = 29). Under these experimental conditions, we tested the effects of Cl removal from the bathing solution on macula densa pHi. As shown in Fig. 1, a reduction in [Cl]B to 8 mmol/l ("bath low chloride") caused intracellular alkalinization, whereas readdition of Cl caused a rapid recovery of pHi (75% of the total decrease in pHi occurred in <40 s). Preincubation with 5 x 104 mol/l DIDS, a blocker of anion exchange, for 15 min reduced the magnitude of increase in pHi on Cl removal and decreased the slope of pHi recovery. Further evidence that these changes in pHi were due to anion exchange and that they also required HCO3, in addition to Cl, came from the finding that omission of carbon dioxide/bicarbonate from both lumen and bath solutions nearly abolished pHi recovery (Fig. 2). In addition, basolateral administration of the cell-permeable carbonic anhydrase inhibitor ethoxzolamide (104 mol/l) reduced base efflux during the pHi recovery phase, i.e., basolateral Cl readdition. Also, on complete removal of Na+ from both apical and basolateral solutions, cell alkalinization was still observable on removal of basolateral Cl (Fig. 3). Finally, depolarization of the macula densa basolateral membrane with an elevation in basolateral potassium concentration ([K+]B) from 5 to 50 mmol/l and clamping the membrane potential with inclusion of 105 mol/l valinomycin to the bath alkalinized macula densa cells (Fig. 4A) by 0.12 ± 0.02 (n = 8) pH units but failed to influence the initial net base efflux and the magnitude of change in pHi on readdition of basolateral Cl (Fig. 4B). From these experiments, we conclude that macula densa cells exhibit basolateral voltage- and Na+-independent chloride/bicarbonate antiport activity.
Inhibition of macula densa basolateral chloride/bicarbonate antiporter by DIDS. Macula densa cells were incubated for 10 min at various concentrations of DIDS (from 2 x 107 to 5 x 104 mol/l) and were then acidified by reductions in [Cl]B. The magnitude and rate of basolateral Cl-dependent pHi recovery were then measured (Fig. 5). Significant inhibition was achieved only at DIDS concentrations higher than 104 mol/l. These data are consistent with a DIDS-resistant Cl/HCO3 antiporter isoform at the macula densa basolateral membrane.
Immunolocalization of AE2 isoform. AE2 immunolabeling of rabbit kidney was found in basolateral domains of macula densa cells as previously described in rat using the same antibody (10). Figure 6 shows AE-2 expression at the basolateral membrane domain of macula densa cells.
Possible role of basolateral chloride/bicarbonate antiporter in macula densa pHi regulation. On increases in luminal sodium concentration ([Na+]L), macula densa cells undergo rapid intracellular alkalinization, mediated by apically located sodium/hydrogen exchange (9, 20). Whether the basolateral Cl/HCO3 antiporter, as an intracellular acid loader, participates in modulating increases in macula densa pHi, in response to elevations in [Na+]L, is unknown. We performed experiments to test whether blocking the basolateral Cl/HCO3 antiport with DIDS magnifies the increase in macula densa pHi on elevations in L from 0 to 100 mmol/l (solutions "perfusion no NaCl" and "perfusion high NaCl"; Table 1). As shown on Fig. 7, preincubation with DIDS significantly increased the elevation in pHi on increases in L.
DISCUSSION
Immunohistochemical studies by Alper et al. (2, 5, 29) reported that macula densa cells express a high abundance of AE2 at their basolateral membrane. Although evidence demonstrating functional activity of AE2 has been lacking, its possible role in macula densa cell physiology has been the subject of some speculation (27). As discussed by Schnermann and Briggs (27), this anion exchanger may play a role in HCO3 reabsorption as well as in the regulation of macula densa pHi. In the present study, we have now identified Na+- and voltage-independent Cl/HCO3 antiport activity at the basolateral membrane of macula densa cells.
In the first series of experiments, we observed a rise in macula densa pHi on reductions in [Cl]B. At a baseline pHi of 6.95, [HCO3]i is calculated to be 10 mmol/l with an extracellular [HCO3] of 27 mmol/l. [Cl]i is estimated to be 10 mmol/l based on previous measurements of macula densa [Cl]i in the absence of luminal Cl but normal Cl containing Ringer solution in the bath (25, 26). This means that there is an approximately threefold extra- to intracellular HCO3 concentration gradient, whereas there is a 12-fold extra- to intracellular Cl concentration gradient. Thus, under these conditions, electroneutral Cl/HCO3 exchange would favor Cl uptake and HCO3 extrusion across the macula densa basolateral membrane. On reductions in [Cl]B to 8 mmol/l, there would be a reduction or perhaps even reversal of the outside-to-inside Cl gradient, causing cessation of bicarbonate extrusion or even bicarbonate influx, thereby leading to cellular alkalinization (Fig. 1). On readdition of basolateral Cl, pHi rapidly falls, indicating bicarbonate extrusion driven by the reestablishment of the outside-to-inside Cl gradient. The initial base efflux, under these conditions, is considered to be a good indicator of Cl/HCO3 antiport activity. The relatively low baseline pHi of 6.95 can be explained by the absence of Na+ in the bath solution acting through the Na+/H+ exchanger. Because chloride/bicarbonate exchangers were described to be inhibited by low pHi (28), the observed changes in pHi with reductions in [Cl]B might have been even larger in the presence of basolateral Na+. The fact, that even in the complete absence of Na+, reductions in [Cl]B evoked reversible macula densa cell alkalinization (Fig. 3) strongly suggests that this acid-base pathway is not occurring via Na+/H+ exchangers or Na+-dependent Cl/HCO3 antiporter.
To further explore the nature of this Na+-independent, Cl-dependent transport system, we tested the HCO3 dependence of Cl-induced changes in pHi. Complete removal of CO2/HCO3 from the perfusate and bath solutions (with consequent removal of intracellular CO2) blocked cell alkalinization obtained with Cl removal, indicating that extracellular and/or intracellular HCO3 is an essential substrate for macula densa basolateral Cl/base exchange. In addition, ethoxzolamide, a membrane-permeable inhibitor of cytoplasmic carbonic anhydrase, reduced Cl/base exchange (Fig. 2), suggesting that macula densa cells can generate HCO3 and that the carbonic anhydrase-generated HCO3 is necessary for full activation of macula densa basolateral Cl/base exchange. In this regard, carbonic anhydrase activity in the cytoplasm of rabbit macula densa cells has been reported (8).
Changes in pHi with basolateral chloride removal and readdition can result from either Cl/HCO3 exchange or could be due to parallel, membrane potential-coupled Cl and HCO3 conductances (31). There are basolateral Cl-conductive pathways in macula densa cells, one of which is responsible for basolateral membrane depolarization in response to increased apical NaCl entry and elevations in [Cl]i (17). There is also a much larger basolateral anion conductance in macula densa cells that is permeable to large ions, including ATP (3, 13). In the present studies, depolarizing and clamping the macula densa basolateral membrane potential with high K+-containing solution and the K+ ionophore valinomycin, respectively, did not affect [Cl]B-induced alterations in pHi. This suggests that the effect of changes in [Cl]B on macula densa cell pHi is not mediated by changes in membrane potential (Fig. 4) and therefore does not occur through ion conductances.
On the other hand, the initial basolateral depolarization-induced alkalinization of the macula densa cells suggests that there is a voltage-dependent acid-base transporter in the macula densa basolateral membrane. We can speculate that via depolarization of the macula densa basolateral membrane, the driving force for HCO3 exit through a yet to be identified anion channel decreases, which leads to intracellular alkalinization. In summary, these results support the existence of a Na+-independent electroneutral Cl/HCO3 exchanger at the basolateral membrane of macula densa cells.
High concentrations of the nonspecific bicarbonate transport inhibitor DIDS reduced the magnitude of change in pHi and the maximal rate of base efflux on chloride readdition (Fig. 5), which is consistent with the presence of a relatively DIDS-resistant isoform in the macula densa basolateral membrane. This low sensitivity to inhibition by stilbene disulfonate derivatives is considered to be a hallmark of the AE2 isoform (18). Also, immunohistological studies have shown the preferential, robust expression of the AE2 isoform in macula densa cells of various rodent species (2, 10, 29). The present studies have extended these findings with the demonstration of AE2 at the basolateral membrane of rabbit macula densa (Fig. 6). These results suggest that macula densa basolateral Cl/HCO3 exchange could be mediated by AE2; however, these studies do not rule out the possibility that other bicarbonate transporters, such as the members of SLC26 family, could be involved. Thus far, SLC26 proteins have been localized to the proximal tubule (11) and the collecting duct (19, 22).
Macula densa cells undergo intracellular alkalinization on increases in luminal Na+ concentration, mediated by the apical Na+/H+ exchanger NHE2 (9, 20). Because Cl/HCO3 exchange is regarded as an acid loader (4), and its activity is increased by a rise in pHi, it seemed reasonable to hypothesize that basolateral Cl/HCO3 exchange contributes to macula densa pHi regulation by buffering L-induced elevations in pHi. This possibility was tested in the last series of experiments, in which we found that increased pHi responses were observed with inhibition of macula densa basolateral Cl/HCO3 exchange by high concentrations of DIDS (Fig. 7). Elevations in L should result in macula densa cell alkalinization through the sodium/hydrogen exchanger. This elevation in pHi should be greater in the presence of DIDS as this drug prevents bicarbonate exit across the basolateral membrane. These results suggest that Cl/HCO3 exchange may prevent excessive elevations/fluctuations in macula densa pHi in response to increases in luminal Na+ concentration.
Recent reports by Wang et al. (30) and Kovacs et al. (15) have suggested a role for macula densa pHi in nitric oxide generation, which may modulate tubuloglomerular feedback and release of renin. Much of the current focus has been on the role of Na+/H+ exchangers in mediating changes in pHi induced by [Na+]L. The present studies suggest that macula densa basolateral Cl/HCO3 exchange may also contribute to L-dependent macula densa signaling by helping to modulate the pHi messenger system.
In summary, these findings demonstrate the existence of Na+-independent Cl/HCO3 exchange at the macula densa basolateral membrane, which could be mediated by AE2. Furthermore, they suggest that Cl/HCO3 exchange may contribute to the regulation of macula densa cell pHi and participate in macula densa signaling.
GRANTS
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant 32032 to P. D. Bell, NIDDK Grant 064324, American Heart Association Scientist Development Grant 0230074N, and American Society of Nephrology Carl W. Gottschalk Research Scholar Grant to J. Peti-Peterdi. The Water and Salt Research Center at the University of Aarhus directed by Prof. Sren Nielsen is established and supported by the Danish National Research Foundation (Danmarks Grundforskningsfond). Support of the Hungarian Scientific Research Fund (OTKA) Grant T037524 to A. Zsembery is also acknowledged.
ACKNOWLEDGMENTS
The authors are grateful to S. M. Wall for providing the AE2a/b antibody. I. M. Paulsen and I. M. Jalk are thanked for expert technical assistance with immunohistochemistry. The authors also thank M. Yeager for secretarial assistance.
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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