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J Am Soc Nephrol 11:1791-1797, 2000
© 2000 American Society of Nephrology

Effect of Luminal Atrial Natriuretic Peptide on Chloride Reabsorption in Mouse Cortical Thick Ascending Limb

Inhibition by Endothelin

CLAIRE BAILLY

Department of Cellular Biology, CEA-Saclay, Gif sur Yvette, France.

Correspondence to Dr. Claire Bailly, URA 1859, Bât. 520, SBCe/DBCM, CEA-Saclay, 91191 Gif sur Yvette Cedex, France. Phone: 33 1 69 08 97 60; Fax: 33 1 69 08 35 70; E-mail: teboul{at}dsvidf.cea.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Abstract. Insofar as neutral endopeptidase inhibition has afforded evidence for a tubular luminal action of atrial natriuretic peptide (ANP), the present study was undertaken to investigate a possible effect of the peptide on chloride reabsorption (JCl) in thick ascending limb (TAL). Luminal addition of ANP to in vitro microperfused cortical TAL (CTAL) significantly decreased JCl with a threshold and a maximum concentration of 10-12 M and 10-9 M, respectively. A similar effect of 10-9 M ANP was observed in medullary TAL (MTAL). The effect of luminal ANP was significantly reduced by HS-142-1, a specific inhibitor of guanylyl cyclase receptor, and by H-8, a protein kinase G inhibitor, but was not affected by the protein kinase C inhibitor bisindolylmaleimide I. Unexpectedly, the effect of ANP was not additive with that of endothelin (ET), a peptide that was previously shown to decrease JCl in TAL through a calcium-independent, protein kinase C—mediated pathway. Indeed, ET-1 (10-8 M in the lumen) significantly decreased JCl and prevented a further effect of ANP on the same tubule. Similarly, the decrease of JCl induced by simultaneous addition of ET and ANP was not higher than that obtained with each agent alone. Conversely, the inhibitory effect of ANP was enhanced in the presence of cyclic guanosine monophosphate (cGMP; 10-6 M in the lumen). ET-1 significantly attenuated the ANP-stimulated generation of cGMP in microdissected CTAL and failed to prevent a further decrease of JCl promoted by a permeant cGMP analogue. It is concluded that luminal ANP decreased Cl reabsorption in mouse CTAL and MTAL. This effect was abrogated by ET-1 as a result of the inhibition of ANP-stimulated cGMP generation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Atrial natriuretic peptide (ANP) participates in the regulation of extracellular fluid volume, partly through inhibition of renal sodium reabsorption (1). Although cortical (2) and inner medullary (3,4) collecting tubules represent the main renal sites of ANP action, two studies indicate that the medullary part (M) of the thick ascending limb of Henle's loop (TAL) contributes to ANP-elicited natriuretic effect (5,6). In these latter studies (5,6), ANP was tested at the basolateral face of the tubular segments. Nevertheless, the recent development of inhibitors of neutral endopeptidase has afforded some lines of evidence for a luminal action of the peptide (7,8,9). Neutral endopeptidase, an ectoenzyme located in the brush border membrane of the proximal tubule, serves as a major route for the degradation of filtered peptides, including ANP (10). Administration of neutral endopeptidase inhibitors increases urinary excretion of ANP, of cyclic guanosine monophosphate (cGMP), and of sodium and decreases plasma renin activity. Such effects might result in part from an inhibitory effect of luminal ANP on NaCl reabsorption in TAL, leading to increased sodium delivery to downstream sites of the nephron, especially to the macula densa.

The present work was undertaken to investigate a possible action of luminal ANP on chloride reabsorption (JCl) in mouse TAL, mainly in its cortical part (CTAL). This work also evaluated the possible interaction between ANP and endothelin 1 (ET) because (1) luminal and basolateral ET inhibit JCl in the mouse TAL through a protein kinase C- dependent, calcium-independent pathway (11), and (2) neutral endopeptidase also degrades ET (12). Finally, it was verified that luminal cGMP decreased JCl in CTAL as previously reported in the medullary TAL (MTAL), through a pathway that did not involve activation of protein kinase G (6).

The main results indicated that luminal ANP decreased chloride reabsorption along the whole TAL, an effect prevented by ET but not by cGMP. The action of ET was related to an inhibition of the ANP-stimulated cGMP accumulation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Microperfusion Experiments
CTAL and MTAL were microperfused in vitro following the technique routinely used in our laboratory (6). Briefly, male Swiss mice that weighed 18 to 20 g were killed by cervical dislocation and exsanguinated. Coronal slices were cut from both kidneys and immediately immersed in a cold perfusion solution (for composition, see below) with 0.1% bovine serum albumin added. CTAL (1 = 495 ± 16 µm, n = 67) and MTAL (1 = 607 ± 104 µm, n = 5) were dissected from the medullary rays of the cortex and from the inner stripe of the outer medulla, respectively. Each tubule was then transferred to a Lucite chamber thermostatically maintained at 36.0 ± 0.1°C, with a flow rate of approximately 5 ml/min.

Each perfused tubule was allowed to equilibrate for 1 h (CTAL) or 30 min (MTAL). During the experiment, the luminal fluid was collected every 10 min. After a 30-min control period, the required agent was added to the lumen followed by one or two 30-min experimental periods, as mentioned in the text. The luminal fluid was manually changed with a syringe, under microscopic observation, with 2 ml of a solution delivered for approximately 4 min and followed by an equilibration period so that the entire maneuver lasted more than 10 min. It has been previously shown (6) and verified in this work (see Results section) that this protocol only slightly alters JCl in time-control tubules.

The composition of the perfusion solution was as follows: 140 mM NaCl, 4 mM KCl, 0.8 mM MgSO4, 0.44 mM NaH2PO4, 0.33 mM Na2HPO4, 1 mM MgCl2, 1 mM CaCl2, 10 mM N-hydroxyethylpiperazine-N1-ethanesulfonic acid, and 10 mM urea. Glucose (5mM) was added to the bathing solution. Solutions were devoid of bicarbonate because it is not required for NaCl reabsorption in the mouse CTAL (13). All solutions were adjusted to pH 7.38 to 7.41.

Chloride concentrations in collected fluid (Cc) and perfusate (Cp) were determined by microelectrometric titration. The tubular flow rate (V) was calculated from the volume of the collected sample, assuming that water reabsorption was negligible in TAL. The length (L) of the perfused tubule was measured with an eyepiece micrometer at 160 x magnification. The net chloride flux was calculated as JCl = (Cc - Cp) x V/L and expressed in pmoles/min per mm tubular length.

Fifteen groups of tubules were studied (one tubule per mouse):

  1. Two-phase experiments performed on CTAL

  2. Three-phase experiments performed on CTAL

  3. Two-phase experiments performed on MTAL

For each period, data from the 10-min collections at equilibrium were pooled and considered as a single point. Values are expressed as means ± SEM. Statistical significance was evaluated between two periods within each series by the paired t test. For comparing the different series, results were expressed as the percentage of JCl inhibition versus the control period of each tubule. Statistical treatment was the one-way analysis of variance followed by Fisher's Least Significant Difference test, using as parameter the difference of log (JCl) between the control and experimental periods. The criterion for statistical significance was P < 0.05.

cGMP Content
cGMP content was determined by RIA Kit NEN (Life Science Products, Inc., Boston, MA) in tubules microdissected after collagenase dissociation of kidney tissue. Nine male Swiss mice were anesthetized with sodium pentobarbital (0.1 mg/10 g body wt). The left kidney was perfused in situ via the abdominal aorta with 5 ml of incubation solution containing 140 mM NaCl, 4 mM KCl, 1 mM CaCl2, 0.8 mM MgSO4, 0.44 mM NaH2PO4, 0.33 mM Na2HPO4, 4 mM NaHCO3, 5 mM glucose, 10 mM CH3COONa, and 20 mM HEPES. Collagenase (151 U/mg) 0.3% wt/vol and BSA 0.1% wt/vol were added. Thin pyramids were excised along the corticopapillary axis of the kidney and were incubated for 10 to 15 min at 35°C in the incubation solution containing 0.1% collagenase.

For cGMP determinations, the tubular segments were transferred to a slide and photographed for subsequent determination of their length. Tubular segments (approximately 70 mm total length) were pooled onto a slide containing 2 µl of incubation solution added with phosphodiesterase inhibitors, namely IBMX (10-3 M), an unspecific phosphodiesterase inhibitor; 8-methoxymethyl IBMX (10-4 M), an inhibitor specific for the phosphodiesterase degrading both cAMP and cGMP (type I); and zaprinast (10-4 M), an inhibitor specific for the cGMP phosphodiesterase (type V and IX). Each sample was preincubated for 10 min at 30°C and then incubated for 4 min at 35°C in the presence of 2 µ1 of either the solution alone (baseline), or ANP (10-7 M) or ANP plus ET-1 (10-6 M). The reaction was stopped by transferring the sample into a tube containing 25 µl of a 5% (vol/vol) mixture of formic acid and absolute ethanol. After evaporation, acetate buffer was added and cGMP was determined by radioimmunoassay after acetylation. The limit of detection was 1.5 fmole of cGMP per tube.

In each experiment, comparison between two conditions was evaluated by paired t test. In six experiments, baseline, ANP, and ANP plus ET were tested on the same animal.

Endothelin, ANP, H-89, and H-8 were purchased from Calbiochem (La Jolla, CA). Bisindolylmaleimide was purchased from Research Biochemicals International (Natick, MA). HS-142-1 was a gift from Kyowa Hakko Kogyo Co, Ltd (Japan). All other products were from Sigma Chemical Co. (St. Louis, MO).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Inhibitory Effect of Luminal ANP on JCl
In CTAL, luminal ANP 10-9 M significantly decreased JCl from 170.8 ± 26.8 to 101.6 ± 14.0 pmoles/min per mm (P < 0.01, Figure 1, middle columns), an effect associated with a significant decrease of the chloride concentration difference between the perfusate and collected fluid from 17.4 ± 3.8 to 10.8 ± 2.2 mM (P < 0.02). This inhibitory effect of luminal ANP was significantly higher than the slight decrease observed in time-control tubules, in which the luminal fluid was changed with the same solution devoid of hormone (7.6 ± 1.9% versus 39.6 ± 2.0%, P < 0.001, Figure 1, left columns). When added to the bath at the concentration of 10-9 M, ANP induced a similar effect (30.7 ± 3.5%, Figure 1, right columns). Finally, the inhibitory effect of luminal ANP was also observed in MTAL (Table 1).



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  		Figure 1. Effect of atrial natriuretic peptide (ANP) on chloride reabsorption (JCl) in cortical thick ascending limb (CTAL). (N), number of tubules. In two groups (left and middle columns), the luminal fluid was changed after the control period (C) with a solution either of identical composition (C') or containing ANP at the concentration of 10-9 M (ANP1). In the third group (right columns), 10-9 M ANP was added to the bath (ANPbl). *, significantly different from the preceding period.

 

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  		Table 1. Effect of luminal ANP on chloride reabsorption in MTALa
 

When different concentrations of ANP were tested on separate groups of CTAL, a dose-dependent effect was observed from 10-12 M to 10-9 M, a concentration for which the maximal effect was reached (Figure 2). This latter concentration has been used in the following experiments.



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  		Figure 2. Inhibitory effect of different concentrations of ANP on JCl in CTAL. The ordinate (in percentage) represents the decrease of JCl between the control and experimental periods in the same tubule. *, significantly different from the preceding value, by analysis of variance (ANOVA; see Materials and Methods section for statistical analysis).

 

The luminal effect of ANP was largely blocked by HS-142 to 1 and by H-8, at the respective concentrations of 10-8 and 10-6 M (Figure 3). Indeed, the inhibition of JCl observed between control and experimental periods in the presence of these agents was not substantially different from that observed in the time-control tubules described above (10.8 ± 3.8% and 11.1 ± 3.4% versus 7.6 ± 1.9%, for HS-142 to 1, H-8, and control groups, respectively). Conversely, the effect of ANP was virtually unaffected by bisindolylmaleimide I (38.0 ± 3.4% compared with 39.6 ± 2.0%, the ANP-exposed tubules presented above). This agent was added to the lumen at the concentration of 10-7 M since the control period onward as far as we have previously shown that this protocol completely blocked the luminal effect of ET in mouse TAL (11).



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  		Figure 3. Effect of ANP on JCl in CTAL, in the presence of inhibitors of protein kinase C, protein kinase G, and guanylyl cyclase-coupled ANP receptor. The ordinate (in percentage) represents the decrease of JCl between the control and experimental periods in the same tubule. ANP (10-9 M) was added to the lumen during the experimental period; bisindolylmaleimide I (Bis, 10-7 M) was present in the lumen since the control period onward; H-8 (10-6 M) was present in the bath since the control period onward; HS-142-1 (10-8 M) was added to the lumen simultaneously with ANP. *, significantly different from the group Bis, by ANOVA (see Materials and Methods section for statistical analysis).

 

Absence of Additivity of Luminal ANP and Luminal ET Effects
Two protocols were used. In the first one, the agents were added sequentially to the same tubules during two consecutive experimental periods; in the second one, both agents were simultaneously added to the lumen during the experimental period. The results indicated that ET-1, at the maximum concentration of 10-8 M, significantly decreased JCl from 190.4 ± 24.4 to 110.5 ± 14.9 pmoles/min per mm (P < 0.05) and fully abolished a further effect of ANP on the same tubule (110.5 ± 15.0 pmoles/min per mm, Figure 4). Because both ANP and ET exert quantitatively similar effects on JCl, one can question whether the absence of the effect of ANP may result from the inability of JCl to be lowered below a baseline value. However, addition of 10-6 M cGMP to the lumen significantly lowered JCl from 216.5 ± 23.6 to 122.5 ± 16.7 pmoles/min per mm (P < 0.01) and did not prevent a further ANP-induced decrease of JCl to 76.7 ± 13.3 pmoles/min per mm (P < 0.001, Figure 4).



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  		Figure 4. Effect of sequential addition to the lumen of either endothelin and ANP or cyclic guanosine monophosphate (cGMP) and ANP on JCl in CTAL. Experiments were performed on two groups of five tubules. Left columns: after the control period (C), endothelin 1 (ET) and ANP were added sequentially to the lumen at the concentration of 10-8 M and 10-9 M, respectively. Right columns: after the control period (C), cGMP, at the concentration of 10-6 M, and ANP were added sequentially to the lumen. *, significantly different from the preceding value.

 

Similar results were obtained with the second protocol: Simultaneous addition of ANP and ET decreased JCl from 231.6 ± 52.5 to 145.8 ± 34.7 pmoles/min per mm (Figure 5), a 37.9 ± 3.3% inhibition similar to that obtained with ANP alone (39.6 ± 2.0%, presented above). In contrast, concomitant addition of ANP and cGMP decreased JCl from 185.6 ± 33.8 to 70.7 ± 12.3 pmoles/min per mm, representing a 60.1 ± 3.6% inhibition significantly higher than that obtained with ET + ANP alone (P < 0.01, Figure 5).



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  		Figure 5. Effect of simultaneous addition to the lumen of ANP and either ET or cGMP on JCl in CTAL. Experiments were performed on two groups of five tubules. After the control period (C), ANP was added to the lumen at the concentration of 10-9 M in the presence of either ET at the concentration of 10-8 M (left columns) or cGMP at the concentration of 10-6 M (right columns). *, significantly different from the preceding value (paired t test); §, significantly different from the other value.

 

Two hypotheses might account for the nonadditivity between the effects of ANP and ET. First, these two agonists might share a common signaling pathway at a step beyond the activation of their respective protein kinase. Indeed, we have previously shown that ET-1 inhibits JCl in the mouse CTAL via a protein kinase C-dependent, calcium-independent pathway (11), and we verified in the present study that this inhibitory effect was not significantly modified by H-8 (33.4 ± 4.7% inhibition of JCl, n = 4). Second, ANP and ET might interact negatively with each other. This hypothesis was tested by investigating a possible effect of ET on ANP-stimulated cGMP production (Figure 6). The increase in cGMP accumulation observed in the presence of 10-7 M ANP (0.068 ± 0.010 versus 0.029 ± 0.010 fmole/mm, P < 0.01, for ANP and control, respectively) was significantly attenuated by 10-6 M ET-1 (0.042 ± 0.007 fmole/mm, P < 0.02), although reaching a value still higher than the baseline (P < 0.05). The concentrations of ANP used here corresponded to the maximum effect reported by others on cGMP production (15). Indeed, as is discussed below, it must be noted that the cGMP accumulation was very low. However, this cannot be accounted for by a technical pitfall because in the same experiments, ANP increased cGMP accumulation in glomeruli from 2.9 ± 0.7 to 22.8 ± 1.5 fmole/glomerulus (n = 10).



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  		Figure 6. Inhibitory effect of ET on ANP-stimulated cGMP production in CTAL. (N): number of animals from which CTAL were obtained. On six animals, cGMP accumulation was determined under the three conditions in the same experiment. The effect of ANP (10-7 M) was compared either with the basal value or with ANP added with ET (10-6 M), determined in the same experiment. *, significantly different from the basal value; §, significantly different from ANP.

 

That ET inhibited ANP action at a step proximal to cGMP accumulation was further verified by evaluating the additivity of the effects of ET and the permeant cGMP analogue 8-bromo cGMP. In the presence of 10-8 M luminal ET-1, JCl was decreased significantly by 40.3 ± 4.2% (from 146.7 ± 19.2 to 92.9 ± 7.5 pmoles/min per mm, P < 0.05), a value similar to that obtained in the ET + ANP group (41.8 ± 4.4%). In contrast to ANP, however, 8-bromo cGMP, added to the bath at the concentration of 10-4 M, further decreased JCl by 34.4 ± 3.6% (to 58.0 ± 10.1 pmoles/min per mm, P < 0.01, Figure 7). This inhibitory factor was similar to the effect of 8-bromo cGMP already reported in our laboratory (6,16).



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  		Figure 7. Time dependence of JCl in the presence of ET and ANP or ET and 8-bromo cGMP in CTAL. Ordinate represents JCl expressed as the percentage of the second value obtained during the control period, which, in most cases, corresponded to the steady state. JCl corresponding to 100% was 153.8 ± 22.3 (n = 5) and 201.4 ± 24.3 (n = 5) pmoles/min per mm (not significant), for 8-bromo cGMP and ANP groups, respectively. At times indicated by the arrows, ET (10-8 M) was added to the lumen followed by either ANP in the lumen (10-9 M, [UNK]) or the permeant cGMP analogue 8-bromo cGMP in the bath (10-4 M, {circ}) *, significantly different from 8Br-cGMP (see Materials and Methods section for statistical analysis).

 


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The main results of the present study indicate that luminal ANP decreased JCl in CTAL and MTAL. In CTAL, this effect was impaired by ET through an inhibition of ANP-stimulated cGMP production.

The presence of luminal guanylyl cyclase-coupled ANP receptors along the nephron has been strongly suggested by the effects of in vivo administration of neutral endopeptidase inhibitors (7,8,9). Furthermore, ANP receptors have been detected in the apical membrane of the thin limbs of Henle's loop and the cortical collecting tubule of the rat (17). Despite this, only one study has reported an inhibitory effect of luminal ANP on sodium transport in microcatheterized inner medullary collecting duct in the rat (4). Thus, taken together, this study (4) and the present one represent the demonstration of a functional action of luminal ANP in tubular segments of the nephron.

The luminal effect of ANP observed here may be of physiologic relevance because it was obtained at the concentration of 10-12 M. Indeed, assuming that ANP found in urine is provided only by the filtered hormone, this concentration is of the same order as the one calculated in TAL from the urinary excretion rate under basal conditions and three orders of magnitude lower than the one reached after administration of neutral endopeptidase inhibitors (8). Taken together, present and previous results from our laboratory in the mouse (6) as well as a work from Nonoguchi et al. (5) in the rat provide compelling evidence for an inhibitory effect of luminal and basolateral ANP on chloride reabsorption along the whole TAL. Moreover, because urodilatin shares the same receptors as ANP and exerts a similar effect as ANP on JCl in MTAL (6), similar results would have been obtained with the renal endogenous peptide.

The present data indicated that the effects of ANP and ET were not additive, although these two agents triggered different signaling pathways. It has been previously shown that luminal and basolateral ET-1 inhibit chloride reabsorption in the mouse TAL through a protein kinase C activation, independent of any increase in intracellular calcium (11). It has been further verified in the present work that the effect of ANP on JCl was not mediated by protein kinase C or that of ET by protein kinase G (see Results section). That the ET effect on JCl was not altered by a protein kinase G inhibitor may argue against a stimulation of nitric oxide generation by this hormone, in contrast to what has been reported in the rat (18). Species differences may be responsible for these discrepancies. The lack of additivity of ANP and ET effects is accounted for in part by the inhibition by ET of ANP-generated cGMP accumulation because (1) ET failed to prevent a further inhibitory effect on JCl of a permeant cGMP analogue and (2) this effect was directly observed by determining cGMP content. That the action of ANP may be negatively controlled by ET through a protein kinase C-mediated inhibition of guanylyl cyclase activity has already been established on vascular smooth muscle cells and endothelial cells (19,20). It must be noted that when cGMP content was determined in tubular samples, the agonists were present in the incubation medium. Nevertheless, it may be assumed that the luminal surface was also accessible to these agents inasmuch as, first, microscopic observation revealed that most microdissected tubules displayed a fairly open lumen and, second, numerous studies report that electrolyte transport through the apical Na+ -K+ -2Cl- cotransporter in MTAL suspensions is inhibited by incubation with selective blockers such as furosemide or bumetanide. This point notwithstanding, ANP (6); present data) exerts the same effect on JCl via similar signaling pathways on both sides of the epithelium, a pattern also observed for ET (11).

That ET inhibited ANP-induced cGMP accumulation in the presence of phosphodiesterase inhibitors argues for an inhibition of cGMP synthesis. Nevertheless, this conclusion must be mitigated given the very low levels of cGMP accumulation determined in CTAL by us and others (5,15,16), suggesting the presence of remaining phosphodiesterase activity. It is noteworthy that addition of zaprinast, an inhibitor specific for the cGMP-dependent phosphodiesterase (types 5 and 6) barely improved the accumulation rate of nucleotide, as compared with the studies in which IBMX alone was used (5,15). Among the nine phosphodiesterase families as yet described (21), some of them turned out to be unexpectedly insensitive to IBMX, an inhibitor considered to be unspecific for these enzymes. Therefore, a possible stimulation by ET of a yet unknown cGMP-dependent phosphodiesterase, insensitive to both IBMX and zaprinast, cannot be precluded with certainty.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
This work reported an inhibitory effect of luminal ANP in TAL. Compelling evidence is thus afforded that both ANP and ET, from either apical or basolateral membranes, and cGMP from the lumen decrease JCl in TAL (6,11). However, because the presence of the nucleotide enhanced the inhibitory effect of ANP, ET impaired it at a step proximal to cGMP accumulation. The physiologic relevance of such a negative regulation is not obvious because both hormones exhibit similar effects on JCl. Some evidence, however, suggests that these two agents promote opposite effects on renin secretion—inhibition for ANP (10) and activation for ET (22)—which is inversely related to the chloride delivery to the macula densa. Although this issue was not addressed in the present study, one can speculate that an ET-induced regulating process could prevent the decrease in renin secretion that might be expected from the action of ANP on JCl.


   Acknowledgments
 
This work was supported by grants from the Center National de la Recherche Scientifique and from the Commissariat à l'Energie Atomique. The technical assistance of Huguette Moysan is gratefully acknowledged. The author is indebted to Jean-Baptiste Michel for fruitful discussion.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication July 30, 1999. Accepted for publication March 17, 2000.




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