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Am J Physiol Regul Integr Comp Physiol 276: R1792-R1797, 1999;
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Vol. 276, Issue 6, R1792-R1797, June 1999

Neonatal rabbit proximal tubule basolateral membrane Na+/H+ antiporter and Clminus /base exchange

Mehul Shah1, Raymond Quigley1, and Michel Baum1,2

1 Departments of Pediatrics and 2 Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present in vitro microperfusion study examined the maturation of Na+/H+ antiporter and Cl-/base exchanger on the basolateral membrane of rabbit superficial proximal straight tubules (PST). Intracellular pH (pHi) was measured with the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein in neonatal and adult superficial PST. Na+/H+ antiporter activity was examined after basolateral Na+ addition in tubules initially perfused and bathed without Na+. Neonatal Na+/H+ antiporter activity was ~40% that of adult segment (9.7 ± 1.5 vs. 23.7 ± 3.2 pmol · mm-1 · min-1; P < 0.001). The effect of bath Cl- removal on pHi was used to assess the rates of basolateral Cl-/base exchange. In both neonatal and adult PST, the Cl-/base exchange activity was significantly higher in the presence of 25 mM HCO-3 than in the absence of HCO-3 and was inhibited by cyanide and acetazolamide, consistent with Cl-/HCO-3 exchange. The proton flux rates in the presence of bicarbonate in neonatal and adult tubules were 14.1 ± 3.6 and 19.5 ± 3.5 pmol · mm-1min-1, respectively (P = NS), consistent with a mature rate of Cl-/HCO-3 exchanger activity in neonatal tubules. Basolateral Cl-/base exchange activity in the absence of CO2 and HCO-3, with luminal and bath cyanide and acetazolamide, was greater in adult than in neonatal PST and inhibited by bath DIDS consistent with a maturational increase in Cl-/OH- exchange. We have previously shown that the rates of the apical membrane Na+/H+ antiporter and Cl-/base exchanger were approximately fivefold lower in neonatal compared with adult rabbit superficial PST. These data demonstrate that neonatal PST basolateral membrane Na+/H+ antiporter and Cl-/base exchanger activities are relatively more mature than the Na+/H+ antiporter and Cl-/base exchangers on the apical membrane.

Cl-/HCO-3 exchanger; Cl-/OH- exchanger; Na+-bicarbonate cotransporter; renal development; intracellular pH; microperfusion


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

INTRACELLULAR pH (pHi) plays an important role in many biological activities (32). Various cellular processes affected by pHi include transepithelial solute transport, enzyme function, and cell proliferation (3, 15, 20). Steady-state pHi of epithelial cells is determined by the balance between the rates of intracellular acid loading and acid extrusion. Intracellular acid loading occurs by passive movement of protons into the cell, cellular metabolism, and fluxes of acids and bases (32). There are a number of transport mechanisms involved in the regulation of epithelial cell pHi (3, 10, 21, 28). The Na+/H+ antiporter and Cl-/HCO-3 exchangers are nearly ubiquitous among mammalian cells and play an important role in pHi regulation in a number of cells (1, 23, 25, 26, 30, 33, 38). Basolateral Na+/H+ antiporter and Cl-/HCO-3 exchange activity in the kidney has been demonstrated in the proximal tubule, thick ascending limb of Henle, medullary collecting duct, and glomerular mesangial cells (11-13, 16, 18, 19, 25, 27, 31, 35, 40). Na+/H+ and Cl-/base exchange are on the basolateral membrane of developing nephrons (4). Parallel Na+/H+ and Cl-/HCO-3 exchange activity on the basolateral membrane play a role in cell volume regulation by mediating cellular NaCl uptake and thereby preventing cell shrinkage when exposed to a hypertonic extracellular milieu (9, 36, 37).

We have recently demonstrated that the neonatal rabbit superficial proximal straight tubule (PST) has a lower rate of active and passive NaCl transport than the adult segment. The rates of apical Na+/H+ antiporter and Cl-/base exchanger, which mediate net NaCl transport across the apical membrane, were approximately fivefold lower in the neonatal segment compared with the adult segment (34). In the present in vitro microperfusion study, we examined the rates of basolateral membrane Na+/H+ antiporter, Cl-/base exchange, and Na+-HCO-3 cotransporter activity in neonatal and adult superficial PST. We find that there is a maturational increase in basolateral membrane Na+/H+ antiporter and Na--HCO-3 cotransporter activity but that basolateral Cl-/base exchange in the presence of 25 mM HCO-3 is the same in adult and neonatal PST.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Isolated segments of adult and neonatal (14-21 days of age) rabbit superficial PST (S2 segments) were perfused as previously described (5, 14, 34). Briefly, tubules were dissected in Hank's balanced salt solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO4, 0.33 Na2HPO4, 0.44 KH2PO4, 1 MgCl2, 10 tris(hydroxymethyl)aminomethane hydrochloride, 0.25 CaCl2, 2 glutamine, and 2 lactate at 4°C. Tubules were transferred to a 0.2-ml chamber, in which the bathing solution was preheated to 38°C. The tubules were perfused with concentric glass pipettes.

The solutions used in these experiments are shown in Table 1. The fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) was used to measure pHi as described previously (2, 5, 27, 34). We measured pHi with a Nikon inverted epifluorescent microscope attached to a PTI Ratiomaster at a rate of 30 measurements/s. A variable diaphragm was placed over the area to be measured. To calculate pH from the ratio of fluorescence (F500/F450), a nigericin calibration curve was performed as previously described (2, 5). There was no difference in the calibration curves of adult and neonatal PST.

                              
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  		Table 1.   Solutions used in pHi studies

Tubules were incubated with the initial luminal and bathing solutions for >= 10 min after loading with 5 × 10-6 M acetoxymethyl BCECF and had a constant pHi for several minutes before the measurement of the transporter activity. The bathing fluid was changed at a rate of >= 5 ml/min. We measured dpHi/dt from the slope of the change in pHi immediately after a bathing fluid change. Steady-state pHi values were present within 90 s after a bathing fluid exchange but were followed for several minutes to ensure a steady-state pHi was achieved.

Apparent buffer capacity was measured as previously described with NH3-NH+4 (5, 26, 32, 34). Solutions (B and D) used in the experiments for measurement of apparent buffer capacity did not contain Na+ or Cl- to inhibit all acidification mechanisms caused by Na+- and Cl--dependent transporters. In the absence of HCO-3, buffer capacity was 28.1 ± 5.0 mM/pH in neonatal PST and 43.0 ± 6.6 mM/pH in adult PST (n = 6 for both groups, P = NS). Buffer capacity in the presence of HCO-3 was estimated as the sum of the above buffer capacity and the HCO-3 buffer capacity. The latter was calculated as 2.3 · [HCO-3i] (27, 32), where [HCO-3i] is the intracellular bicarbonate concentration. The buffer capacities in the presence of HCO-3 were 80.4 ± 5.8 and 94.4 ± 4.6 mM/pHi in neonatal and adult PST, respectively (P = NS).

Tubular volume was calculated from the measured inner and outer tubular diameters at ×400 magnification with an eyepiece reticle. The tubular volumes of neonatal and adult PST were 5.3 ± 0.2 × 10-10 and 10.2 ± 0.4 × 10-10 l/mm, respectively (P < 0.001).

Proton flux rates1 (JH, in pmol · mm-1 · min-1) resulting from a bathing fluid change were calculated with the following formula
<IT>J</IT><SUB>H</SUB> = <FR><NU>dpH<SUB>i</SUB></NU><DE>d<IT>t</IT></DE></FR> ⋅ <FR><NU>V</NU><DE>mm</DE></FR> ⋅ &bgr;
where dpHi/dt is the rate of initial change in pHi after a bathing fluid change, V is the tubular volume in liters, and beta  is the buffer capacity.

Data are expressed as means ± SE. ANOVA and the Student's t-test for paired and unpaired data were used to determine statistical significance.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We first examined the rate of basolateral Na+/H+ antiporter activity in neonatal and adult proximal straight tubules (PST). We measured the net JH in response to addition of 140 mM Na+ to the bathing fluid (solution C) in tubules initially perfused and bathed without Na+ (solution B). These experiments were performed in absence of Cl- to prevent the Cl-/base exchanger from attenuating pHi changes during the bathing fluid change. The steady-state pHi for neonatal and adult tubules are shown in Table 2. The neonatal PST pHi was somewhat lower than that of the adult segment (0.10 > P > 0.05). Despite the lower pHi, JH in the neonatal PST was ~40% that of the adult segment as shown in Fig. 1 (P < 0.001).

                              
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  		Table 2.   Effect of basolateral Na+ addition on pHi in adult and neonatal PST



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  		Fig. 1.   Proton flux rates (JH) in response to addition of bath Na+ in adult and neonatal proximal straight tubules (PST) initially perfused and bathed in absence of Na+. * P < 0.001 vs. adult PST.

We next examined Cl-/base exchange in neonatal and adult tubules in the presence of 25 mM HCO-3 (solutions E and F). The initial pHi were comparable in neonatal and adult segments (Tables 3 and 4). As shown in Fig. 2, there was no significant difference between the JH of neonatal (14.1 ± 3.6 pmol · mm-1 · min-1) and adult PST (19.5 ± 3.5 pmol · mm-1 · min-1). As shown in Fig. 2, in both neonatal and adult tubules, 0.1 mM bath DIDS inhibited Cl-/base exchange (P < 0.05).

                              
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  		Table 3.   Effect of basolateral Cl- removal on pHi in adult PST


                              
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  		Table 4.   Effect of basolateral Cl- removal on pHi in neonatal PST



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  		Fig. 2.   JH in adult and neonatal PST in response to bath Cl- removal in bicarbonate-containing solutions and in presence of 0.1 mM basolateral DIDS. * P < 0.05 vs. corresponding value of Cl- base + 25 mM HCO-3.

In the next series of experiments, we examined the rate of basolateral Cl-/base exchange in neonatal and adult PST in absence of exogenous HCO-3. Tubules were initially perfused and bathed in a HEPES-buffered Cl--containing solution without Na+ (solution A). In the experimental period, Cl- was removed from the bathing fluid (solution B) and JH was measured. Tables 3 and 4 show the pHi values in neonatal and adult tubules. There was no significant difference in the initial pHi of neonatal and adult tubules. As shown in Fig. 3, JH was significantly lower in neonatal compared with adult PST (P < 0.05). However, JH was significantly higher in both neonatal and adult tubules in presence of HCO-3 compared with that in HEPES-buffered solutions (P < 0.05), consistent with a Cl-/HCO-3 exchanger on the basolateral membrane of both neonatal and adult superficial PST.


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  		Fig. 3.   JH in adult (A) and neonatal (B) PST in response to bath Cl- removal in presence of 25 mM HCO-3, HEPES-buffered solutions (no HCO-3, and in presence of luminal and bath cyanide and acetazolamide (± 0.1 mM bath DIDS). * P < 0.05 vs. Cl- base + 25 mM HCO-3 and Cl-/base + 2 mM cyanide + 0.1 mM acetazolamide; + P < 0.05 vs. corresponding adult value; ddager  P < 0.05 vs. Cl/base + 2 mM cyandide + 0.1 mM acetazolamide.

We next examined the activity of Cl-/base exchange in the presence of 2 mM cyanide and 0.1 mM acetazolamide to assess the relative contribution of endogenous CO2 and HCO-3 in mediating the Cl-/base exchange. Tubules were initially perfused and bathed in HEPES-buffered high-Cl- solution (solution A) with 2 mM cyanide and 0.1 mM acetazolamide, and during the experimental period bath Cl- was removed. As shown in Tables 3 and 4, the initial pHi were comparable between the neonatal and adult groups (P = NS). As shown in Fig. 3, JH was about 70% lower in neonatal (P < 0.001) and 55% lower in adult tubules (P = 0.01) compared with that in absence of cyanide and acetazolamide, suggesting that endogenous CO2 and HCO-3 were contributing significantly to the Cl-/base exchange on the basolateral membrane of both neonatal and adult PST.

The residual Cl-/base exchange with 2 mM cyanide and 0.1 mM acetazolamide could be a result of continued endogenous CO2 production or of a Cl-/OH- exchanger. We next examined the effect of 5 mM cyanide and 0.1 mM acetazolamide on the Cl-/base exchange in neonatal and adult PST. The JH in neonatal and adult proximal straight tubules were 1.2 ± 0.1 and 5.4 ± 0.1 pmol · mm-1 · min-1, respectively. These rates were not different from the JH in the presence of 2 mM cyanide and 0.1 mM acetazolamide.

We next examined if the residual Cl-/base exchange in the presence of 2 mM cyanide and acetazolamide was inhibited by 0.1 mM DIDS. As seen in Tables 3 and 4, bath DIDS almost totally abolished the pHi change with removal and addition of bath Cl-. As shown in Fig. 3, bath DIDS resulted in a significant decrease in Cl-/base exchange. These data suggest that there is a CO2-HCO-3-independent, DIDS-inhibitable anion exchanger on the basolateral membrane consistent with a Cl-/OH- exchanger. The rate of Cl-/base exchange on the basolateral membrane in the presence of cyanide and acetazolamide was greater in adults than in neonates, consistent with a maturational increase in Cl-/OH- exchange.

In the final series of experiments, we examined the activity of the Na+-HCO-3 cotransporter. PST were initially perfused and bathed in bicarbonate-containing solutions in the presence of 50 mM ethylisopropylamiloride (EIPA) without Na+ (solution F) as previously described (22). EIPA was added to inhibit the basolateral Na+/H+ exchanger. We then added 140 mM Na+ in the presence of EIPA, and the effect on pHi was examined. As shown in Table 5, the initial pHi was comparable in adult and neonatal tubules. Figure 4 shows that Na+-HCO-3 cotransporter activity was significantly less in neonatal PST than in adult tubules. In both groups the effect of Na+ addition was inhibited by 0.1 mM bath DIDS (P < 0.05).

                              
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  		Table 5.   Basolateral Na+-HCO-3 cotransporter activity: effect of basolateral Na+ addition on pHi in presence of EIPA and EIPA + DIDS



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  		Fig. 4.   JH in adult and neonatal PST in bicarbonate-buffered solutions in response to bath Na+ addition in the presence of 50 mM ethylisopropylamiloride ± 0.1 mM DIDS. * P < 0.01 vs. corresponding value of Na+-HCO-3 cotransport activity without DIDS; + P < 0.05 vs. corresponding neonatal value.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In this study we examined the rates of basolateral Na+/H+ antiporter, Na+-HCO-3 cotransporter, and Cl-/base exchange in neonatal PST and compared these to the adult segment. There was a twofold maturational increase in basolateral membrane Na+/H+ antiporter activity and a similar maturational increase in Na+-HCO-3 cotransporter activity. In the presence of bicarbonate, the rates of basolateral Cl-/base exchange were comparable in the neonatal and adult segments.

Two isoforms of the Na+/H+ antiporter have been localized to the proximal tubule. NHE3 is the apical Na+/H+ antiporter and is responsible for most of the luminal proton secretion in this segment (7, 39). NHE1 is localized to the basolateral membrane of the proximal tubule and has a wide distribution in mammalian tissue (8, 39). We have previously examined the maturation of apical membrane Na+/H+ antiporter activity in both proximal convoluted tubules and PST (5, 34). In both segments, there is a maturational increase in antiporter activity. In the PST, there is a fivefold increase in Na+/H+ antiporter activity during postnatal maturation (34). Consistent with these findings is the fourfold increase in renal cortical NHE3 mRNA and protein abundance during postnatal maturation (6).

The maturation of proximal tubule basolateral Na+/H+ antiporter activity has not previously been examined. However, we have previously demonstrated that rabbit renal cortical NHE1 mRNA and protein abundance, the proximal tubule basolateral Na+/H+ exchanger (8), does not change significantly during postnatal maturation (6). Thus there is a clear discordant maturational pattern between NHE1 and NHE3. In the PST we find that there is a 2.4-fold increase in Na+/H+ antiporter activity on the basolateral membrane compared with the fivefold increase on the apical membrane. A previous study in rabbit myocardial cells demonstrated comparable Na+/H+ antiporter activity in newborns and adults (29).

The rate of Na+-HCO-3 cotransporter was assessed by measuring the effect of bath Na+ addition in presence of bicarbonate (22). Under these conditions the Na+/H+ antiporter plays a minor role on JH in comparison to the Na+-HCO-3 cotransporter (22). We added EIPA to the solutions to inhibit any small contribution of the Na+/H+ exchanger to the JH as previously described (22). The rate of Na+-HCO-3cotransporter activity was approximately two- to threefold greater in adults than in neonates. In both segments the Na+-HCO-3 cotransporter was inhibited by DIDS. These results agree well with the maturational changes in Na+-HCO-3 cotransporter activity we have previously found in the rabbit proximal convoluted tubule (5). The rate of Na+-HCO-3 cotransporter activity was comparatively greater than the other basolateral membrane transporters studied here because this transporter plays a major role facilitating basolateral membrane bicarbonate exit.

There is a profound difference in the maturational pattern of the apical and basolateral Cl-/base exchangers in this nephron segment. We have previously shown that the apical membrane Cl-/base exchange activity in neonatal rabbit superficial PST was about sixfold lower than in the adult segment. Apical membrane Cl-/base exchange activity was not augmented by 25 mM HCO-3 or 0.5 mM formate, consistent with a Cl-/OH- exchanger (34). In the present study, we found that the Cl-/base activity on the basolateral membrane of both neonatal and adult superficial PST was significantly higher in the presence of 25 mM HCO-3 and was inhibited by cyanide and acetazolamide. These data are consistent with Cl-/HCO-3 exchange mediating a significant portion of basolateral Cl-/base exchange. Kurtz et al. (27) had previously demonstrated that in PST from adult rabbit, apical Cl-/base exchange was via a Cl-/OH- exchange, whereas basolateral exchange was mediated predominantly by a Cl-/HCO-3 exchanger.

In the present study, the neonatal Cl-/HCO-3 exchange activity was comparable to the adult segment, suggesting a relatively mature Cl-/HCO-3 exchange activity on the basolateral membrane of the neonatal superficial PST. In similar experiments, others have shown that the neonatal mammalian myocardium had a fully functional Cl-/HCO-3 exchange activity, which played an important role in pHi regulation (24, 29).

Our results show that there is a significant difference in the Cl-/base exchange activity between neonatal and adult PST in absence of HCO-3. This may, in part, be a result of the higher rate of aerobic metabolism in the adult compared with the neonatal segments (17). To determine the rates of Cl-/base exchange in the absence of endogenously produced CO2 and bicarbonate, we added 2 and 5 mM cyanide and acetazolamide to the luminal and bathing solutions. This produced a significant reduction in both neonatal and adult PST Cl-/base exchange activity consistent with Cl-/HCO-3 exchange fueled by metabolically derived CO2. The residual Cl-/base exchange activity in the presence of 2 mM cyanide and 0.1 mM acetazolamide was not likely caused by continued CO2 generation, inasmuch as 5 mM cyanide did not produce a greater inhibition in Cl-/base exchange activity. Cl-/base exchange activity in the presence of cyanide and acetazolamide was almost entirely inhibited with DIDS, consistent with a basolateral membrane Cl-/OH- exchanger. The residual Cl-/base exchange activity in the presence of cyanide and acetazolamide was significantly greater in adult than in neonatal PST, consistent with a maturational increase in a basolateral Cl-/OH- exchanger. However, the rate of basolateral membrane Cl-/HCO-3 exchange in the presence of HCO-3 was comparable in neonatal and adult PST.

Perspectives

Basolateral membrane Na+/H+ and Cl-/HCO-3 exchangers have been shown to play an important role in cell volume and pH regulation. These functions are necessary for cell homeostasis in both neonatal and adult proximal tubule. These studies are consistent with basolateral Na+/H+ and Cl-/base exchangers being relatively more mature than those present on the apical membrane in the PST. The applicability of these observations to other nephron segments and other species will have to be investigated. In addition, the effect of neonatal and adult transporters on the apical and basolateral membrane to defend against changes in pHi and intracellular volume will need to be investigated in future studies.


    ACKNOWLEDGEMENTS

We are grateful to the secretarial assistance of Janell McQuinn.


    FOOTNOTES

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-41612 (to M. Baum) and DK-02232 (to R. Quigley).

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. §1734 solely to indicate this fact.

1 All proton fluxes are presented as absolute values and expressed as JH in pmol · mm-1 · min-1.

Address for reprint requests and other correspondence: M. Baum, Dept. of Pediatrics, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063.

Received 9 September 1998; accepted in final form 3 March 1999.


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INTRODUCTION
METHODS
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DISCUSSION
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Am J Physiol Regul Integr Compar Physiol 276(6):R1792-R1797
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society


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