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Am J Physiol Renal Physiol 290: F1315-F1319, 2006. First published December 27, 2005; doi:10.1152/ajprenal.00450.2005
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Endothelins

Endothelin-1 stimulates NO production and inhibits cAMP accumulation in rat inner medullary collecting duct through independent pathways

Peter K. Stricklett, Alisa K. Hughes, and Donald E. Kohan

Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah

Submitted 11 November 2005 ; accepted in final form 23 December 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Endothelin-1 (ET-1) inhibition of vasopressin (AVP)-stimulated cAMP accumulation in the collecting duct has been hypothesized to be mediated, at least in part, by nitric oxide (NO). To examine this, the effect of ET-1 on NO production by acutely isolated rat inner medullary collecting duct (IMCD) cell suspensions and the role of NO in mediating ET-1 effects on AVP-stimulated cAMP accumulation were studied. ET-1 dose dependently (first evident at 100 pM ET-1) increased IMCD NO production as determined by DAF-FM fluorescence. ETB receptor (BQ-788), but not ETA receptor (BQ-123), antagonism blocked this effect. Nonspecific NO synthase (NOS) inhibitors [NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine] or NOS-1 inhibitors (SMTC or VNIO) inhibited the ET-1 response, whereas NOS-2 or NOS-3 inhibitors (L-NAA or 1400W) were ineffective. ET-1 also increased cGMP accumulation. ET-1 caused a 35% reduction in AVP-stimulated cAMP levels; however, this response was not affected by L-NAME or SMTC. The addition of L-arginine, NADPH, tetrahydrobiopterin, or tempol (to reduce superoxide-dependent conversion of NO to peroxynitrate) did not affect the response. NO donors (SNAP or spermine NONOate), at concentrations that stimulated DAF-FM fluorescence and increased cGMP levels, did not alter AVP-stimulated cAMP accumulation in the IMCD cell suspensions. In conclusion, ET-1 stimulates IMCD NO production through activation of the ETB receptor and NOS-1. However, neither ET-1-mediated NO production nor NO donors inhibit AVP-stimulated cAMP accumulation, indicating that NO does not mediate ET-1 inhibition of cAMP production by the IMCD.

nitric oxide synthase; cyclic guanosine 5'-monophosphate; endothelin B receptor

ENDOTHELIN-1 (ET-1) inhibits water reabsorption by the collecting duct in vitro (17, 18, 26) and in vivo (9). This effect is due to activation of the endothelin B receptor in cortical collecting duct (CCD) and inner medullary collecting duct (IMCD) and to reduction of vasopressin (AVP)-stimulated cyclic AMP (cAMP) accumulation (5, 14, 27). The mechanisms by which ET-1 decreases agonist (AVP or forskolin)-stimulated cAMP levels have been partially clarified and shown to involve protein kinase C and pertussis toxin-sensitive pathways, but not cyclooxygenase metabolites (14). Another proposed mediator of ET-1 inhibition of cAMP accumulation in the collecting duct is nitric oxide (NO). ET-1 stimulates NO production by multiple cell types (15, 22). NO can reduce AVP-stimulated osmotic water permeability in CCD (7). This effect has been ascribed to NO-augmented cGMP via soluble guanylate cyclase, activation of cGMP-dependent protein kinase, and resultant inhibition of AVP-stimulated cAMP accumulation (8). Despite this evidence, there has been no direct analysis of the role of NO in mediating ET-1 inhibition of AVP-stimulated cAMP levels in collecting duct. Several issues need addressing. First, it is uncertain whether ET-1 does, in fact, stimulate NO production by the collecting duct. Acute exposure (1–10 min) of microdissected rat IMCD to ET-3 (relatively selective agonist of the endothelin B receptor) did not alter cGMP levels (20), whereas specific endothelin A or B receptor agonists reduced nitric oxide synthase 3 (NOS-3 or endothelial NOS) in cultured rat IMCD cells (31). In contrast, preliminary data suggest that ET-1 acutely (10 min) increases NO-dependent cGMP accumulation in an IMCD cell line (IMCD-K2) and stimulates NO release (4-h exposure) (24). Second, if ET-1 does stimulate NO release by collecting duct, the relevant NOS isoform(s) is/are unknown. Collecting duct, and particularly the IMCD, expresses all three NOS isoforms (25, 29). Notably, the IMCD expresses more NOS than any other nephron segment (3, 25), and NOS is present in much higher levels (up to 25-fold) in the medulla than the cortex (21). Third, there have been no studies examining the effect of NO blockade on ET-1 inhibition of AVP-stimulated cAMP accumulation in collecting duct. Consequently, the current study was undertaken to determine whether NO mediates, at least in part, ET-1 downregulation of agonist-stimulated cAMP levels in collecting duct.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Materials. 4-Amino-5-ethylamino-2',7'-difluorescein (DAF-FM) was obtained from Molecular Probes (Eugene, OR); ET-1, BQ-123, and BQ-788 from Peptides International (Louisville, KY); S-methyl thiocitrulline (SMTC), NG-amino-L-arginine (L-NAA), L-N5-(1-imino-3-butenyl)-ornithine (VNIO), NG-nitro-L-arginine methyl ester (L-NAME), NG-monomethyl-L-arginine (L-NMMA), and N-[3-(aminomethyl)benzyl]acetamidine (1400W) from Alexis Biochemicals (San Diego, CA); cAMP and cGMP enzyme immunoassay (ELISA) kits from R&D Systems (Minneapolis, MN); and collagenase from Invitrogen (Carlsbad, CA). All other reagents were obtained from Sigma (St. Louis, MO) unless stated otherwise.

Cell isolation. IMCD cells were isolated from male Sprague-Dawley rats weighing ~200 g (Sasco, St. Louis, MO) using a modification of a previously described procedure (14). Renal inner medullas were minced and incubated with 1 mg/ml collagenase and 0.1 mg/ml deoxyribonuclease (type I) in Krebs buffer (140 mM NaCl, 14 mM glucose, 4.7 mM KCl, 2.5 mM CaCl2, 1.8 mM MgSO4, 1.8 mM KH2PO4) for 45 min in a 37°C shaking water bath. The sample was centrifuged at 400 g for 5 min, washing in Krebs containing 10% bovine serum albumin, then washed twice in Krebs alone. Tubule fragments were resuspended in Krebs for NO, cAMP, or cGMP measurements.

NO assay. Acutely isolated IMCD cells were loaded with 10 µM DAF-FM for 30 min at 37°C. Cells were then washed, aliquoted into 96-well plates, and allowed to rest for 30 min to maximize deacetylation of the dye by intracellular esterases. Cells were then subjected to various experimental conditions. At the end of the experimental period, 20% of the cells from each well were removed for determination of protein using the Bradford assay. Fluorescence in the remaining cells on the 96-well plate was determined on a Molecular Devices Gemini EM Microplate reader at excitation/emission of 496/524 nm. All inhibitors were added at the time of the dye load and left throughout the experiment. All samples were normalized to total cell protein.

cAMP assay. Acutely isolated IMCD cells were incubated with 1 mM isobutylmethylxanthine (IBMX) for 30 min. Cells were then incubated in the presence of inhibitors for 30 min at 37°C, and then ET-1 was added for up to an additional 30-min incubation at 37°C. Next, AVP (1 nM) was added for 10 min at 37°C after which the reaction was stopped by the addition of ethanol. Samples were frozen and then dried. Dried samples were resuspended in a minimal volume of water and 20% of the sample was removed for protein determination by the Bradford assay. cAMP levels were determined using a commercially available ELISA, and absorbance was read with a Molecular Devices SpectramaxII microplate reader. All samples were normalized to total cell protein.

cGMP assay. Acutely isolated IMCD cells were incubated in 1 mM IBMX for 30 min. Cells were then incubated for up to 30 min at 37°C in the presence of various experimental agents. The reaction was stopped with ethanol, and samples were frozen and then dried. Dried samples were resuspended in a minimal volume of water and protein determined as for the cAMP assay. cGMP levels were determined using a commercially available ELISA; all samples were normalized to total cell protein.

Statistics. All comparisons were made using one-way ANOVA with the Bonferroni correction. P < 0.05 was taken as significant. Data are expressed as means ± SE.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
ET-1 stimulates IMCD NO production. ET-1 (10 nM) stimulated NO production by acutely isolated rat IMCD cells (Fig. 1). This effect was evident after 30 min and was maintained out to 4 h, albeit tending to diminish by this latter time point. ET-1 also dose dependently stimulated IMCD NO production (Fig. 2). The lowest effective concentration of ET-1 for this 30-min exposure was 100 pM. Baseline NO levels were barely detectable and incubations had to be carried out to 30 min to see NO production. Neither baseline nor ET-1-stimulated NO production was altered by addition of 0.1–2 mM L-arginine, 100 µM NADPH, 10 µM tetrahydrobiopterin, or 0.1–10 mM tempol (to reduce superoxide interaction with NO), either alone or in combination, when these agents were present throughout the incubation. The ET-1 effect on NO was relatively modest (140% over baseline), albeit significant.


Figure 1
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  		Fig. 1. Time course of endothelin-1 (ET-1; 10 nM) stimulation of nitric oxide (NO) production by acutely isolated rat inner medullary collecting duct (IMCD) cells; n = 6 each data point. *P < 0.01 vs. no added ET-1 for same time of incubation.

 

Figure 2
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  		Fig. 2. Dose response of ET-1 (30-min incubation) stimulation of NO production by acutely isolated rat IMCD cells; n = 8 each data point. *P < 0.01 vs. no added ET-1.

 
ET-1 stimulates IMCD NO production through ETB receptor and NOS-1. The stimulatory effect of ET-1 on IMCD NO production was completely abolished by incubation with an ETB receptor-specific antagonist (BQ-788) but was not affected by the presence of an ETA receptor-specific antagonist (BQ-123; Fig. 3). Both BQ-788 and BQ-123 were used at 1 µM, a concentration shown to be specific for ETB and ETA receptors, respectively (14, 30). The increase in DAF-FM fluorescence was due to NO as nonspecific blockade of all NOS isoforms with L-NAME abolished the ET-1 effect (Fig. 4). SMTC, a relatively specific NOS-1 (neuronal NOS) inhibitor with about a 20-fold greater affinity for NOS-1 compared with other NOS isoforms (6), blocked ET-1-stimulated NO production. SMTC was used at a concentration of 1 µM; this compares with its IC50 of 0.31 µM for inhibition of NOS-1 in rat brain slices (6). In contrast, L-NAA, a NOS-2/3 inhibitor with relatively lower NOS-1 affinity (1), did not affect the ET-1 response (Fig. 4). 1400W at 0.5 µM, a NOS inhibitor with an IC50 for NOS-2 (inducible NOS) of about 0.23 µM (vs. IC50 of 7.3 µM for NOS-1 and 1,000 µM for NOS-3) (1), did not affect ET-1-stimulated NO production (Fig. 5). Similar to SMTC, V-NIO at 1 µM, a relatively specific NOS-1 inhibitor with a Ki of 0.1 µM for NOS-1, 12 µM for NOS-3, and 60 µM for NOS-2 (2), prevented ET-1 augmentation of NO levels (Fig. 5). Thus, while no one agent is specific enough to make definitive conclusions, taken together these results indicate that NOS-1 mediates ET-1-enhanced NO production by IMCD.


Figure 3
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  		Fig. 3. Effect of ETA receptor (BQ-123, 1 µM) or ETB receptor (BQ-788, 1 µM) on ET-1 (10 nM) stimulation of NO production by acutely isolated rat IMCD cells. Cells were exposed to vehicle or ET receptor antagonists for 30 min, and then media or ET-1 was added in the presence of vehicle or receptor antagonists for another 30 min; n = 12 each data point. *P < 0.0025 vs. no added ET-1.

 

Figure 4
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  		Fig. 4. Effect of nonspecific nitric oxide synthase (NOS) inhibition (L-NAME, 1 mM), NOS-1 inhibition (SMTC, 1 µM), or NOS-2/3 inhibition (L-NAA, 10 µM) on ET-1 (10 nM) stimulation of NO production by acutely isolated rat IMCD cells. Cells were exposed to vehicle or NOS inhibitors for 30 min, and then media or ET-1 was added in the presence of vehicle or NOS inhibitors for another 30 min; n = 8 each data point. *P < 0.01 vs. no added ET-1.

 

Figure 5
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  		Fig. 5. Effect of NOS-1 inhibition (VNIO, 1 µM) or NOS-2/3 inhibition (1400W, 0.5 µM) on ET-1 (10 nM) stimulation of NO production by acutely isolated rat IMCD cells. Cells were exposed to vehicle or NOS inhibitors for 30 min, and then media or ET-1 was added in the presence of vehicle or NOS inhibitors for another 30 min; n = 8 each data point. *P < 0.01 vs. no added ET-1.

 
ET-1 inhibition of AVP-stimulated cAMP production is not mediated by NO. As previously reported (5, 14, 27), ET-1 reduced AVP-stimulated cAMP accumulation in IMCD cells by ~25–30% (Fig. 6). Note that this and all subsequent cAMP (and cGMP) studies were done in the presence of IBMX as cyclic nucleotides could not be detected in the absence of phosphodiesterase inhibition. Neither L-NAME nor SMTC, at the same concentrations that completely blocked ET-1-stimulated NO production, prevented ET-1 inhibition of the AVP response (Fig. 6). This suggested that ET-1 did not act through NO, that ET-1-stimulated NO levels were too small to be effective, and/or that NO does not affect cAMP accumulation under these conditions. To test this, IMCD cells were exposed to NO sources or donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine (SNAP). Notably, the spermine NONOate concentration (1 µM) was the same as that reported to inhibit AVP-stimulated cAMP accumulation in isolated rat CCD (8). Neither spermine NONOate nor SNAP had an effect on AVP-stimulated cAMP levels, while ET-1 under the same conditions again was inhibitory by ~30% (Fig. 7). Notably, both spermine NONOate and SNAP stimulated cGMP accumulation in IMCD under the same conditions as used in the studies on their effects on cAMP (Fig. 8). Also, despite the fact that ET-1 and spermine NONOate stimulated cGMP accumulation to similar degrees (Fig. 8), ET-1, but not spermine NONOate, inhibited AVP-augmented cAMP accumulation. Thus ET-1 inhibition of AVP-stimulated cAMP levels in IMCD is not mediated by NO or cGMP production. Furthermore, NO itself does not appear, at least under the conditions studied, to inhibit AVP-stimulated cAMP accumulation.


Figure 6
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  		Fig. 6. Effect of nonspecific NOS inhibition (L-NAME, 1 mM) or NOS-1 inhibition (SMTC, 1 µM) on ET-1 (10 nM) inhibition of AVP-stimulated cAMP accumulation by acutely isolated rat IMCD cells. Cells were exposed to vehicle or NOS inhibitors for 30 min, and then media or ET-1 was added in the presence of AVP (100 pM) and vehicle or NOS inhibitors for 10 min. cAMP was then measured and calculated as cAMP/µg total cell protein; n = 18 each data point. *P < 0.001 vs. no added ET-1.

 

Figure 7
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  		Fig. 7. Effect of NO donors (1 µM spermine NONOate or 20 µM SNAP) or ET-1 (10 nM) on AVP-stimulated cAMP accumulation by acutely isolated rat IMCD cells. Cells were exposed to vehicle, NO donors or ET-1, together with AVP (100 pM) for 10 min, followed by determination of cAMP (calculated as cAMP/µg total cell protein); n = 12 each data point. *P < 0.0025 vs. vehicle alone.

 

Figure 8
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  		Fig. 8. Effect of NO donors (1 µM spermine NONOate or 20 µM SNAP) or ET-1 (10 nM) on cGMP accumulation by acutely isolated rat IMCD cells. Cells were exposed to vehicle, NO donors, or ET-1 for 10 min, followed by determination of cGMP (calculated as cGMP/mg total cell protein); n = 6–8 each data point. *P < 0.01 vs. vehicle alone.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The current study observed that ET-1 stimulates NO production by acutely isolated rat IMCD. Although the degree of NO stimulated by ET-1 was relatively modest (~140% over control), this was sufficient to substantially increase cellular cGMP content to a level comparable to that seen with doses of spermine NONOate previously shown to exert physiological effects through cGMP-dependent pathways (8). Thus ET-1-enhanced NO production by IMCD appears to be of sufficient magnitude to potentially regulate downstream systems. The ET-1 effect occurs by activation of the ETB receptor. This finding is expected as ET-1-dependent NO production has been repeatedly demonstrated to be largely mediated through activation of the ETB receptor (13, 15, 22). The current study also showed that ET-1-induced NOS activity is likely due to involvement of NOS-1. Although none of the NOS inhibitors used are absolutely specific for a given NOS isoform, the finding that VNIO and SMTC inhibited the ET-1 effect, while L-NAA and 1400W did not, strongly suggests that NOS-1 is the relevant isoform. IMCD have been shown in several studies to express all known NOS isoforms (3, 4, 25, 29) (we also confirmed NOS-1, -2, and -3 mRNA presence in our cells but did not show the data as this is well accepted). Interestingly, one study found that NOS-1 is expressed in principal, but not intercalated, cells, at least in the CCD (28). While ET-1 stimulation of NOS-1 activity has not been previously reported in the kidney, ET-1 has been shown to activate NOS-1 (and through ETB receptors) in stellate ganglion and hypothalamus (11, 30). Taken together, the above findings indicate that physiological concentrations of ET-1, via activation of the ETB receptor, can stimulate NOS-1-dependent NO production, leading to cGMP accumulation, in the IMCD. It should be noted that these findings contrast with those previously reported (20) in which ET-3 failed to increase cGMP in microdissected rat IMCD (in the presence of IBMX). The reasons for this difference are uncertain; the details of the conditions used in the previous study are not described.

We observed that addition of L-arginine, tetrahydrobiopterin, NADPH, or tempol did not increase NO production by IMCD, nor did L-NAME, or any other NOS inhibitor employed in this study, decrease basal NO levels. These findings contrast with those previously reported (12) in which L-arginine stimulated, while L-NAME inhibited, basal rat IMCD NO production (both changed by ~20%). The reasons for this difference are uncertain. Basal NO production was less in our study, making changes more difficult to detect. In addition, it is possible that the sensitivity of the prior study was somewhat greater; flow cytometry was used to detect changes in DAF fluorescence.

ET-1-stimulated NO production has been hypothesized to mediate, at least partially, the inhibitory effect of ET-1 on AVP-enhanced cAMP accumulation and water reabsorption in the collecting duct (15, 22). However, we found that ET-1 reduction of AVP-dependent cAMP production was not affected by either relatively specific NOS-1 or nonspecific NOS blockade. Furthermore, NO donors did not alter AVP-stimulated cAMP accumulation, despite increasing cGMP to levels either equal to or greater than that seen with ET-1. Notably, ET-1 inhibition of water reabsorption appears to be primarily determined by its effects on AVP-augmented cAMP levels as ET-1 reduces AVP- but not cAMP-stimulated collecting duct water permeability (17). Furthermore, ET-1 can reduce agonist-enhanced cAMP accumulation in collecting duct in the presence of phosphodiesterase inhibition, as reported in this study and in others (14, 27). Taken together, these studies suggest that ET-1 inhibition of AVP-stimulated cAMP accumulation in collecting duct is not mediated by NO. In addition, the current studies suggest that NO per se does not alter AVP effects on adenylyl cyclase in the collecting duct. Such conclusions are in contrast to the findings by Garcia and colleagues (8) who found that spermine NONOate reduces AVP-stimulated water permeability and cAMP accumulation in isolated, perfused rat CCD. The reasons for these different findings are speculative; however, several possibilities exist. First, our study examined IMCD, while the previous study used CCD. To our knowledge, there are no data indicating differential regulation of AVP-induced cAMP accumulation between these two nephron segments; this possibility merits further exploration. Second, in contrast to the present study, the CCD studies were conducted in the absence of phosphodiesterase inhibition. It is possible, therefore, that NO could be regulating a cAMP phosphodiesterase, perhaps via cGMP-dependent pathways. This possibility could not be tested in IMCD as no cAMP can be detected in the absence of phosphodiesterase inhibition. Taken together, the above considerations indicate that NO, either due to ET-1 stimulation or exogenously administered, does not alter AVP-stimulated cAMP production; the effect of NO from either source on cAMP degradation needs additional investigation.

The current study should not be construed to infer that ET-1 stimulation of NO production is not an important regulator of tubule transport processes. For example, there is clear evidence that ET-1 inhibits thick ascending limb chloride flux through stimulation of NO production by NOS-3 (10, 23). In addition, both ET-1 (16, 26) and NO (19) may inhibit Na reabsorption in the collecting duct; it is possible that this effect of ET-1, which is cAMP independent, is mediated, at least in part, by NO. The present findings underscore the complexity of ET-1 and NO interactions in the nephron and provide further impetus to continue studies examining the relationship of these closely interacting substances in regulating nephron function.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The work conducted in this study was supported by National Institutes of Health Grant R01-DK-96392 (to D. E. Kohan).


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. E. Kohan, Division of Nephrology, Univ. of Utah Health Sciences Center, 1900 East, 30 North, Salt Lake City, UT 84132 (e-mail: donald.kohan{at}hsc.utah.edu)

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.


   REFERENCES
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