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Am J Physiol Renal Physiol 275: F452-F457, 1998;
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Vol. 275, Issue 3, F452-F457, September 1998

Peptide YY inhibits vasopressin-stimulated chloride secretion in inner medullary collecting duct cells

Christopher M. Breen, Peter J. Mannon, and Bruce A. Benjamin

Department of Cell Biology, Duke University Medical Center and Division of Gastroenterology, Department of Veterans Affairs Medical Center, Durham, North Carolina 27710; and Department of Pharmacology and Physiology, Oklahoma State University, College of Osteopathic Medicine, Tulsa, Oklahoma 74107

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

mIMCD-k2 cells are derived from the inner medullary collecting duct of a mouse and exhibit electrogenic sodium absorption and cAMP- and vasopressin (AVP)-stimulated electrogenic chloride secretion [N. L. Kizer, B. Lewis, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F347-F355, 1995; and N. L. Kizer, D. Vandorpe, B. Lewis, B. Bunting, J. Russell, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F854-F861, 1995]. The purpose of the present study was to determine how peptide YY (PYY) affects electrogenic Na+ and Cl- current in mIMCD-k2 cells. Short-circuit currents (Isc) were measured across monolayers of mIMCD-k2 cells mounted in Ussing-type chambers. PYY did not alter baseline Isc, nor did it alter Isc in chloride-free conditions, indicating no effect on electrogenic sodium transport. Baseline chloride current in these cells is low; therefore, chloride short-circuit current (IClsc) was stimulated with AVP (10 nM) added to the basolateral surface and 10 µM amiloride added to the apical surface. Although apical applications of PYY had no effect, basolateral application of PYY caused attenuation of IClsc, with the maximal inhibitory dose (100 nM) causing 52 ± 1.3% inhibition (IC50 = 0.11 nM). Inhibition by PYY of IClsc is mediated through the Y2 receptor subtype, as PYY-(3-36) was the only PYY analog tested that caused inhibition and was equipotent to PYY. Inhibition by PYY of IClsc was abolished following incubation with pertussis toxin. We also show that PYY inhibits AVP-stimulated cAMP accumulation, with a maximal inhibitory dose (100 nM) causing a 38% ± 6% inhibition (IC50 = 0.16 nM), comparable to inhibition by PYY of IClsc. We conclude that PYY acts through either Gi or Go to inhibit adenylate cyclase activity, leading to a decrease in AVP-stimulated chloride current.

short-circuit current; chloride secretion; arginine vasopressin; adenosine 3',5'-cyclic monophosphate

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

PEPTIDE YY (PYY) is a 36-amino acid peptide first isolated from the porcine intestine (36). It has subsequently been identified in the intestinal mucosa of ileum, colon, and rectum in many species including human, dog, rat, and rabbit (13, 14, 22, 23, 25, 35-37). PYY has strong homology with both neuropeptide Y (NPY) and pancreatic polypeptide, with which it shares certain common receptors.

PYY is released into the circulation by the gut, primarily in response to feeding (30, 38). PYY-(3-36), which is a specific agonist for the Y2 receptor, appears to form a significant amount of PYY circulating postprandially (17). Although most studies concerning the action of PYY have focused on the gastrointestinal system, both Y1 and Y2 receptors for PYY have been demonstrated in the kidney (8, 26, 34). Ohtomo et al. (28) have shown that the Y2-specific agonist NPY-(13-36) stimulates Na+-K+-ATPase activity in the renal proximal tubule. PYY and NPY also affect renal vascular function, with these effects being associated with the Y1 receptor subtype (6, 26; C. A. Blaze, S. R. Vigna, P. J. Mannon, A. R. Kherani, and B. A. Benjamin, unpublished observations). These findings suggest that the gut may play a role in modulating renal function in the postprandial state.

Preliminary studies in our lab demonstrated the presence of NPY/PYY receptors on renal epithelial mIMCD-k2 cells. These cells are derived from the initial segment of the mouse inner medullary collecting duct (IMCD) and exhibit cAMP- and vasopressin (AVP)-stimulated chloride secretion (20, 21). PYY receptors are coupled to cyclase inhibition and have been shown to inhibit cAMP-dependent chloride secretion (3, 10). The purpose of the present study was to determine the effect of PYY on basal and AVP-stimulated chloride secretion in mIMCD-k2 cells. Results from these studies demonstrate that PYY inhibits AVP- and cAMP-stimulated chloride secretion in the renal epithelial cell model, mIMCD-k2 cells.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

mIMCD-k2 cells were provided by Dr. B. A. Stanton.

Cell culture. mIMCD-k2 cells were cultured in tissue culture flasks coated with Vitrogen plating medium containing human fibronectin (1 mg/ml), 1% Vitrogen 100, and placed in an incubator maintained at 37°C and gassed with 5% CO2-95% air. The cells were grown in DMEM supplemented with 1 nM aldosterone, 5% fetal bovine serum, 2 mM L-glutamine, 50 U/ml penicillin, and 50 µg/ml streptomycin. Medium was changed every 48 h.

Permeable supports. mIMCD-k2 cells were harvested from confluent culture flasks by trypsinization (0.05% in HBSS) and reseeded onto 24-mm polycarbonate membranes (Costar). The medium was changed every 48 h. Electrical resistance of cell monolayers was monitored using chopstick electrodes (EVOM). All experiments were performed on membranes from the same seeding.

Measurement of short-circuit current. Short-circuit experiments were performed using membranes whose resistance was 400-800 Omega  (4.7 cm2 growth area, 1,500 Omega  · cm2), as measured by chopstick electrodes. Short-circuit current (Isc) was measured by placing Transwell membranes in an World Precision Instruments (WPI) Ussing-type chamber. Voltage was clamped to 0 mV with a WPI DVC 1000 voltage clamp. Bath solutions were maintained at 37°C. Solutions were circulated by gas lift using 5% CO2-95% air. Electrical connections from bath to voltage clamp were made with 3 M KCl-5% agar bridges and Ag-AgCl wires. Positive current represents the net flow of cations from the apical to basolateral bath solutions or the net flow of anions from the basolateral to apical bath solutions. Current output was digitized by a MacLab analog-digital converter and stored on a Macintosh SE computer.

Solutions. Most experiments were done using DMEM as the perfusate. For chloride-free experiments, the following solution was used: 24 mM NaHCO3, 114 mM sodium isethionate, 3 mM KHCO3, 2 mM MgSO4, 0.5 mM CaSO4, 8 mM HEPES, and 5 mM glucose, and adjusted to pH 7.4. In studies to determine chloride current, 50 µM amiloride was added to the apical bath to inhibit sodium channels.

Pertussis toxin sensitivity. mIMCD-k2 monolayers grown on permeable supports were incubated overnight in DMEM culture medium containing 100 ng/ml pertussis toxin (PTX). Membranes were then placed in the Ussing chamber, and chloride secretion was stimulated by the addition of 10 nM AVP under short-circuit conditions.

cAMP assay. Cellular cAMP levels were determined using a nonradioactive cAMP assay kit (Amersham). Confluent monolayers grown on permeable supports were preincubated for 30 min in 0.5 mM IBMX in DMEM prior to the addition of PYY (10-8-10-11 M). Following 5-min incubation with PYY, AVP (10 nM) was added. Following a 15-min incubation in the presence of AVP, the medium was removed, cAMP was extracted in two volumes of ice-cold 65% ethanol, and the samples were then dried down in a vacuum oven prior to resuspension in assay buffer.

Statistics and analysis. Differences between means were compared with Student's t-test or analysis of variance followed by Dunnett's multiple comparisons test (dose-response data; Instat). Curve fits were done using Graphpad Prism. All data are means ± SE.

Reagents. All peptides were purchased from Peninsula Laboratories. Amiloride, forskolin, and aldosterone were all purchased from Sigma Chemical. Sodium isethionate was purchased from Fluka Chemika. The sodium salt of 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP) was purchased from Calbiochem Biochemicals. 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) was purchased from Research Biochemical International.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

PYY effect on Isc. PYY did not alter basal Isc or Isc in chloride-free conditions (data not shown), indicating no effect on active sodium transport. To stimulate chloride secretion, 10 nM AVP was added to the basolateral membrane, and 1 µM amiloride was added to the apical surface. Under these conditions, Isc represents electrogenic chloride secretion (20, 21). Figure 1A shows the stimulated chloride current; the response to AVP is biphasic, with an initial peak followed by a prolonged plateau phase (>30 min). NPPB, a chloride channel blocker added to the apical membrane, inhibits Isc, indicating that the current was due to the activity of chloride channels. Figure 1B shows the effect of PYY on AVP-stimulated chloride secretion. After the plateau phase was reached, addition of PYY to the basolateral membrane caused an attenuation of Isc. Figure 2 shows the dose response for PYY inhibition of chloride current. This inhibition was expressed as percent inhibition of AVP-stimulated current, with 100% stimulation being the AVP plateau level minus the pre-AVP current. Maximal inhibitory doses of PYY (100 nM) caused a 52 ± 1.3% (mean ± SE, n = 3) inhibition of AVP-stimulated chloride current (IC50 = 0.11 nM). Additions of PYY > 0.1 nM caused a significant (P < 0.05) decrease in chloride short-circuit current (IClsc). To test whether order of peptide addition was important, monolayers were treated with PYY (10 nM) for 5 min followed by addition of AVP. This did not significantly alter the magnitude of inhibition by PYY of AVP-stimulated Cl- secretion; i.e., AVP stimulation of chloride current after exposure to PYY attained only 60% of the plateau value in the absence of PYY. Addition of PYY to the apical membrane did not alter Isc (data not shown).


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  		Fig. 1.   A: representative short-circuit current (Isc) showing the effect of 10 nM arginine vasopressin (AVP) added to the basolateral bath. Amiloride (10 µM) was added to the apical bath to inhibit electrogenic Na+ reabsorption. 5-Nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 100 µM), a chloride channel blocker, was added to the apical bath to inhibit chloride secretion. B: representative experiment showing PYY attenuation of AVP-stimulated chloride secretion. PYY (10 nM) was added to the basolateral compartment.


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  		Fig. 2.   Inhibition of AVP-stimulated IClsc by PYY as a function of the concentration of PYY. Values are expressed as percent inhibition, with 100% being the difference between Isc prior to AVP addition and the plateau Isc value at the time of PYY addition. EC50 =1.1 × 10-10 M. Additions of 0.1 mM PYY caused a significant decrease in chloride short-circuit current (IClsc) (P < 0.05). Points are the average of 3 experiments ± SE.

Agonist profile. PYY is known to interact through a number of receptor subtypes. The following receptor analogs were added to the basolateral membrane to determine the receptor subtype responsible for the inhibition by PYY of chloride secretion: pancreatic polypeptide, [Leu31,Pro34]NPY, and PYY-(3-36). A 10 nM dose was chosen because this concentration is ~100-fold greater than the IC50 value for the observed inhibition of Isc and cAMP accumulation. PYY-(3-36) is a Y2-receptor agonist with an IC50 for the Y1 and Y2 receptor of 810 nM (18) and 0.06 nM, respectively. [Leu31,Pro34]NPY is a Y1 agonist with IC50 values for the Y1 and Y2 receptor of 0.8 and 140 nM, respectively (4, 16). Pancreatic polypeptide is a Y4 agonist with an IC50 value that exceeds 100 nM and 1,000 nM for the Y1 and Y2 receptors, respectively (24). Given the IC50 values for the Y1, Y2, and Y4 agonists, the 10 nM dose of peptide is appropriate for determining the receptor subtype when using these three ligands in combination. At the 10 nM dose, PYY-(3-36) was the only analog that caused a change in IClsc. PYY-(3-36) was found to be equipotent to PYY in inhibiting IClsc at 0.1 nM [11.1 ± 2.1% PYY vs. 14.5 ± 3% PYY-(3-36), n = 7], 1 nM [39.0 ± 2.1% PYY vs. 44.0 ± 2.6%, PYY-(3-36), n = 4], and 100 nM [52.3 ± 1.3% PYY vs. 46.2 ± 5.8% PYY-(3-36), n = 3].

Role of PYY in cAMP-dependent chloride secretion. Previous studies have shown that the cell-permeable cAMP analog 8-CPT-cAMP stimulates chloride secretion in mIMCD-k2 cells. The effect of PYY on 8-CPT-cAMP-stimulated chloride secretion was tested by the addition of 100 µM 8-CPT-cAMP to the apical reservoir, which stimulated chloride secretion; PYY (10 nM) was then added to the basolateral membrane. PYY did not attenuate 8-CPT-cAMP-stimulated chloride secretion (5.97 ± 0.34 µA/cm2 pre-PYY vs. 5.97 ± 0.32 µA/cm2 post-PYY, n = 4). The effect of PYY on forskolin-stimulated chloride secretion was also tested. Chloride current was stimulated by the addition of 1 µM forskolin to the apical membrane followed by addition of PYY (10 nM) to the basolateral membrane. Inhibition by PYY of forskolin-stimulated chloride secretion (50.2 ± 3.2% inhibition IClsc) was similar to its degree of inhibition of AVP-stimulated chloride secretion (42.7 ± 4.1% inhibition IClsc).

To test that PYY modulates cellular cAMP levels that may be mechanistically associated with its inhibition of cAMP-stimulated chloride secretion, cell monolayers were exposed to PYY (10-7-10-12 M) for 4 min in the presence of IBMX (0.5 mM) prior to the addition of AVP (10 nM). Figure 3 shows the dose response for PYY inhibition of AVP-stimulated cAMP accumulation expressed as percent maximal cAMP accumulation. Maximal cAMP accumulation was the difference between AVP-treated cells (33 ± 1.5 pmol/mg protein) and basal cAMP levels (2.1 ± 0.23 pmol/mg protein). Addition of 0.1 nM PYY caused a significant (P < 0.01) reduction in cAMP levels, with maximal PYY (100 nM) causing 38 ± 6% inhibition of cAMP levels with an IC50 value of 0.16 nM.


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  		Fig. 3.   Inhibition of AVP-stimulated (10 nM) cAMP generation by PYY as a function of PYY concentration. Values are expressed as percent cellular maximum cAMP, with 100% being the difference between control (nonstimulated) and AVP-stimulated values. Points are the average of 3 experiments ± SE. All membranes were from the same seeding. Addition of 0.1 nM PYY caused a significant (P < 0.05) reduction in cAMP levels. IC50 = 0.15 nM.

PTX sensitivity. AVP is postulated to stimulate IClsc by increasing intracellular cAMP through Gs stimulation of adenylate cyclase. In other cell systems, PYY is known to decrease cAMP levels by Gi-mediated inhibition of adenylate cyclase. Gi inhibition is known to be sensitive to PTX. We therefore tested the effect of PTX on the attenuation by PYY of chloride current. mIMCD-k2 cells were incubated overnight in medium containing 100 ng/ml PTX. PTX incubation did not alter the ability of AVP to stimulate chloride current [2.32 ± 0.30 µA/cm2 for AVP + PTX (n = 8) vs. 2.38 ± 0.26 µA/cm2 for AVP alone (n = 6)]. Figure 4 shows the effect of PTX pretreatment on the attenuation by PYY of AVP-stimulated IClsc. In the absence of PTX, PYY (100 nM) attenuated chloride current by 49.3 ± 1.6%. In the presence of PTX, PYY had no effect on chloride current (0.5 ± 0.12%, 100 nM PYY + PTX, P < 0.05).


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  		Fig. 4.   Effect of preincubating mIMCD-k2 monolayers (~18 h) in medium containing pertussis toxin (100 ng/ml). The ability of PYY to attenuate AVP-stimulated chloride current was significantly reduced (49.3 ± 1.64%, 100 nM PYY, vs. 0.5 ± 0.12%, 100 nM PYY + pertussis toxin; * P < 0.05, n = 5). Pertussis toxin did not affect AVP-stimulated chloride secretion.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

Previous characterization of mIMCD-k2 cells has shown that AVP-stimulated chloride secretion is due to increased cellular cAMP levels leading to activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel (20, 21, 39). Here, we show that 100 nM PYY maximally inhibits AVP-stimulated chloride secretion by mIMCD-k2 cells by up to 52% (IC50 = 0.1 nM). PYY does not affect basal Isc or alter Isc in chloride-free conditions, indicating no effect on active sodium transport. The cell-permeable analog of cAMP, 8-CPT-cAMP, has also been shown to stimulate chloride secretion in mIMCD-k2 cells. Here, we show that PYY does not alter 8-CPT-cAMP-stimulated chloride secretion but does inhibit forskolin-stimulated chloride secretion. These results are consistent with PYY acting at the level of adenylate cyclase to modulate cellular levels of cAMP.

When the effect of PYY on AVP-stimulated cAMP generation was tested, we found that PYY inhibits cAMP generation in a dose-dependent manner, with an IC50 of 0.16 nM, approximately equal to the 0.11 nM value for inhibition of chloride current. Maximal inhibitory doses of PYY (100 nM) caused a 38% inhibition of AVP-stimulated cAMP generation comparable with the inhibition by PYY of IClsc. The inhibition by PYY of IClsc was abolished by preincubation with PTX, consistent with PYY acting through Gi or Go to inhibit adenylate cyclase. This is similar to the inhibition by PYY of chloride secretion in the gut (3, 10) and to the antagonism by NPY of AVP actions in rat cortical collecting tubules where NPY reduces AVP-stimulated hydraulic conductivity (11).

In the present study, we show that the attenuation by PYY of chloride secretion is mediated by the Y2 receptor subtype that recognizes COOH-terminal fragments of PYY. The Y2 receptor is the same subtype that is responsible for activation of the Na+-K+-ATPase activity in the renal proximal tubule of the rat (28, 29). Y2 receptors (IC50 = 0.15 nM, PYY) have also been demonstrated in rabbit proximal tubule (34). We show that PYY attenuates chloride secretion with an IC50 of 0.1 nM. This value is within the range for plasma PYY levels, which rise postprandially to 0.4, 0.2, and 0.05 nM in dogs, rats, and humans respectively (1, 5, 15). In humans, the COOH-terminal fragment PYY-(3-36) accounts for 37% of PYY-like immunoreactivity in the fasting state and 63% in the postprandial state (17). Thus the postprandial increase in PYY levels contain significant amounts of peptide, which would specifically activate Y2 receptors and potentially regulate renal tubular function specifically.

The physiological significance of chloride secretion by cells of the distal collecting duct, as modeled by mIMCD-k2 cells, is not well established. Electrogenic chloride secretion has been proposed as mechanism for NaCl secretion by the IMCD (20, 33). Chloride secretion is a mechanism for NaCl secretion by the shark rectal gland (19), which shares a number of features with mIMCD-k2 cells including cAMP-dependent chloride secretion via apical CFTRs, basolaterally located Na+-K+-ATPases, and basolaterally located Na-K-2Cl cotransporters (32, 39). Although the IMCD is normally associated with net reabsorption of NaCl, the ability of the IMCD to secrete sodium has been shown in microperfused IMCD tubules (33). Atrial natriuretic factor increased the electronegative lumen potential, and this increase in electronegativity was associated with increased bath-to-lumen chloride flux and NaCl secretion (33). AVP stimulates IClsc in mIMCD-k2 monolayers, indicating active Cl- secretion; the effect on lumen negativity or Cl- flux has not been studied, nor has the effect on net NaCl transport been studied. In colonic mucosa, inhibition of chloride secretion, by PYY under short-circuit conditions has been shown to increase net Na and Cl absorption without altering active sodium transport (27). It should be noted that in A6 cells, a Xenopus kidney cell line, vasotocin (the amphibian analog to AVP) has been shown to increase chloride current under short-circuit conditions (40). However, under open-circuit conditions, vasotocin treatment leads to a net uptake of NaCl. In A6 cells, AVP also causes a delayed increase in amiloride-sensitive current, and the increase in chloride secretion is thought to favor Na+ uptake via the activated amiloride-sensitive Na+ channels. In mIMCD-k2 cells, we do not see an increase in amiloride-sensitive current, even after 20 min of AVP treatment, nor do we see any increase in Isc under chloride-free conditions. Thus, in mIMCD-k2 cells, AVP does not increase active transport of sodium necessary for the net increase in NaCl uptake. Although we cannot rule out chloride secretion leading to net NaCl reabsorption, the mechanism that mediates this in A6 cells does not appear to be active in mIMCD-k2 cells.

Because the collecting duct is the terminal segment of the nephron, increased chloride secretion in this segment would result in increased excretion of NaCl (20, 33); i.e., it would be natriuretic. We have shown that PYY inhibits chloride secretion and thus would tend to be antinatriuretic, consistent with its proposed action in the proximal tubule (2) also mediated through the Y2 receptor subtype. This proposed mechanism whereby the inhibition by PYY of active chloride secretion leads to net NaCl absorption has been shown in the gut (27). However, the physiological significance of the actions of PYY on renal function is unclear. A number of in vivo PYY and NPY infusion studies have shown both antinatriuretic action in monkeys (12), as well as natriuretic effects in humans (31). Other studies have shown that PYY can be antinatriuretic when infused at doses that mimic physiological levels, but when infused at higher levels, PYY tended to be natriuretic (7). This report and other work (2, 28) suggest that at the tubular level PYY might exert antinatriuretic effects. The disproportionate rise in Y2 active PYY fragments seen postprandially may represent a mechanism to differentially regulate renal tubular activity without affecting renal vasculature.

    ACKNOWLEDGEMENTS

This work was supported by a Career Development Award from the Department of Veterans Affairs (P. J. Mannon), by the Stanback Fund (P. J. Mannon), and by American Heart Association (North Carolina Affiliate) Award NC95GS20 (B. A. Benjamin).

    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. §1734 solely to indicate this fact.

Address for reprint requests: B. A. Benjamin, Dept. of Pharmacology and Physiology, Oklahoma State Univ., College of Osteopathic Medicine, Tulsa, OK 74107.

Received 30 January 1998; accepted in final form 18 June 1998.

    REFERENCES
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Abstract
Introduction
Methods
Results
Discussion
References

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Am J Physiol Renal Physiol 275(3):F452-F457
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society



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