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Role of prostaglandins in collecting duct-derived endothelin-1 regulation of blood pressure and water excretion

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

Submitted 5 July 2007 ; accepted in final form 2 October 2007

	ABSTRACT

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Collecting duct (CD)-derived endothelin-1 (ET-1) exerts natriuretic, diuretic, and hypotensive effects. In vitro studies have implicated cyclooxygenase (COX) metabolites, and particularly PGE₂, as important mediators of CD ET-1 effects. However, it is unknown whether PGE₂ mediates CD-derived ET-1 actions in vivo. To test this, CD ET-1 knockout (KO) and control mice were studied. During normal salt and water intake, urinary PGE₂ excretion was unexpectedly increased in CD ET-1 KO mice compared with controls. Salt loading markedly increased urinary PGE₂ excretion in both groups of mice; however, the levels remained relatively higher in KO animals. Acutely isolated inner medullary collecting duct (IMCD) from KO mice also had increased PGE₂ production. The increased IMCD PGE₂ was COX-2 dependent, since NS-398 blocked all PGE₂ production. However, increased CD ET-1 KO COX-2 protein or mRNA could not be detected in inner medulla or IMCD, respectively. Inner medullary COX-1 mRNA and protein levels and IMCD COX-1 mRNA levels were unaffected by Na intake or CD ET-1 KO. KO mice on a normal or high-Na diet had elevated blood pressure compared with controls; this difference was not altered by indomethacin or NS-398 treatment. However, indomethacin or NS-398 did increase urine osmolality and reduce urine volume in KO, but not control, animals. In summary, IMCD COX-2-dependent PGE₂ production is increased in CD ET-1 KO mice, indicating that CD-derived ET-1 is not a primary regulator of IMCD PGE₂. Furthermore, the increased PGE₂ in CD ET-1 KO mice partly compensates for loss of ET-1 with respect to maintaining urinary water excretion, but not in blood pressure control.

cyclooxygenase; inner medullary; sodium

Perhaps the most extensive studies on mediation of collecting duct ET-1 actions have involved analysis of the role of PGE₂. ET-1 stimulates PGE₂ accumulation by acutely isolated rat inner medullary collecting duct (IMCD), an effect that is mediated by activation of the ET_B receptor (7). Similarly, ET-1 increases PGE₂ levels in acutely isolated rabbit IMCD (12). ET-1 inhibition of ouabain-sensitive ⁸⁶Rb uptake in acutely isolated rabbit IMCD was abolished by pretreatment with ibuprofen; taken together with the above observations, this finding suggested that ET-1 inhibition of Na/K ATPase activity in IMCD is PGE₂ dependent (12). In contrast, the role of PGE₂ in mediating ET-1 inhibition of CD water transport is less evident. ET-1 inhibition of AVP-dependent cAMP accumulation in acutely isolated rat IMCD, in the presence of phosphodiesterase blockade, was shown to be unaffected by indomethacin pretreatment (7). Furthermore, ET-1 inhibition of AVP-stimulated osmotic water permeability (P_f) in isolated, perfused rat IMCD was not affected by prior exposure to indomethacin, whereas PGE₂ inhibition of AVP-stimulated P_f was unaffected by pretreatment with ET-1 (8). Although not related to a direct CD effect, PGE₂ has been shown to reduce ET-1-induced vasoconstriction of medullary descending vasa recta in rat, thereby potentially increasing medullary blood flow (9). Thus, taken together, these in vitro studies suggest that PGE₂ may mediate, at least in part, ET-1 inhibition of CD Na transport, as well as potentially modulating ET-1 effects on neighboring cells in the medulla (e.g., vasa recta). However, there is no in vivo evidence for a role of PGE₂, or other cyclooxygenase (COX) metabolites, in mediating CD ET-1 actions. Consequently, the current study was undertaken, using mice with CD-specific knockout of ET-1, to assess the in vivo relevance of PGE₂ in mediating CD-derived ET-1 actions.

	MATERIALS AND METHODS

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Transgenic mouse lines. All experiments were performed with approval from the Institutional Animal Care and Use Committees at the University of Utah. CD ET-1 knockout (KO) and littermate control mice were generated utilizing the Cre/loxP system, as previously described (1, 5). Briefly, mice with exon 2 of the ET-1 gene flanked by loxP-sites (floxed) (provided by Dr. Masashi Yanagisawa, Howard Hughes Institute, University of Texas Southwestern Medical Center) were mated with AQP2-Cre mice, containing 11 kb of the mouse aquaporin-2 (AQP2) gene driving expression of Cre recombinase. Female AQP2-Cre mice were mated with male floxed ET-1 mice; female offspring heterozygous for both AQP2-Cre and floxed ET-1 were bred with males homozygous for floxed ET-1. Animals homozygous for floxed ET-1 and heterozygous for AQP2-Cre (CD ET-1 KO) were used in this study. Littermates that were homozygous for the floxed ET-1 gene, but without Cre, were used as control mice. Genotyping was performed as previously described (1). All mice were studied at 3–4 mo of age. All reagents used in studies were obtained from Sigma Chemical (St. Louis, MO) unless stated otherwise.

Chronic telemetry studies. Mice had catheters inserted into the right carotid artery, tunneled subcutaneously, and the attached radio transmitter was localized to the back. Continuous recording of blood pressure (BP) and pulse was performed using telemetry (Data Sciences International, Arden Hills, MN). Two days after the surgery, mice were placed into Hatteras metabolic cages (Cary, NC) and acclimated for 3 days. Mice were fed 10 ml of a normal Na (0.3%) gelled diet that contained all nutrients and water as previously described (1). Hemodynamic values were not recorded during this conditioning period. After the 3-day acclimation period, BP and pulse were determined for 2 consecutive days. Daily gel intake and body weights were measured. Systolic, diastolic, and mean BP, as well as pulse rate, were averaged over the course of each day. At the end of this baseline period, mice were given vehicle alone, NS-398 (15 mg·kg^–1·day^–1 ip), or indomethacin (5 mg·kg^–1·day^–1 ip) while remaining on the gelled normal Na intake. After 3 days of NS-398, indomethacin, or vehicle treatment on a normal Na diet, mice were placed on a high-Na diet for 7 days. The high-Na diet consisted of 10 ml of gelled diet containing 1% Na plus normal saline to drink. Daily weights and telemetry were obtained.

In vivo water and solute excretion studies. Mice were acclimated to metabolic cages and a normal Na gelled diet and then given 2 more days of a normal Na diet. Urine was collected on day 2 of the normal Na diet. Mice were then given vehicle alone, NS-398 (15 mg·kg^–1·day^–1 ip), or indomethacin (5 mg·kg^–1·day^–1 ip) for 3 days while being maintained on the normal Na diet. Urine was collected on the third day of NS-398 or indomethacin treatment. Urine volume was measured and urine osmolality determined using an Osmett II (Precision Systems, Natick, MA).

In vivo PGE₂ and COX studies. Mice were acclimated to metabolic cages and a normal Na gelled diet and then given 2 more days of a normal Na diet followed by 3 days of a high-Na diet as described above. Urine during day 2 of a normal Na diet and day 3 of a high-Na diet was collected and analyzed for PGE₂ and volume. Urine PGE₂ was determined using an enzyme immunoassay kit and the manufacturer's protocol (Cayman Chemicals, Ann Arbor MI). Both kidneys from each mouse were used for determination of inner medullary COX-1, COX-2, and β-actin protein levels (see description below).

In vitro PGE₂ determination. CD ET-1 KO and control mice were treated with 2 days of a normal Na diet followed by 3 days of a high-Na diet (diets as described above). Mice were killed at the end of the normal or high-Na diet periods. IMCD were acutely isolated in a manner similar to that previously described (7). Briefly, inner medulla were minced in Krebs buffer with 1 mg/ml collagenase (Invitrogen, Carlsbad, CA ) and 0.1 mg/ml DNase and then incubated at 37°C for 30 min. IMCD fragments were washed, resuspended in HBSS, and preincubated in vehicle alone or 25 µM NS-398 for 30 min at 37°C. Cells were gently pelleted by spinning at 3,000 rpm in a table-top microfuge for 1 min, and the cell pellets were gently resuspended in HBSS with vehicle alone, 25 µM NS-398, or 10 µM indomethacin and placed back in a 37°C water bath for an additional 30 min. Cells were pelleted at 6,000 rpm for 1 min, aliquots of the supernatant were removed, and PGE₂ was measured as described above. The cell pellet was used for determination of protein by the Bradford assay (Bio-Rad, Hercules, CA). PGE₂ levels were normalized to total cell protein.

Western analysis. Renal inner medulla from normal or high-Na diet CD ET-1 KO and control mice were homogenized in 50 mM Tris·Cl (pH 8.0), 150 mM NaCl, 0.1% SDS, 1% Nonidet P-40, 0.5% sodium deoxycholate, and protease inhibitor cocktail tablets (catalog no. 11697498001; Roche Diagnostics, Indianapolis, IN). Samples were centrifuged at 4,000 g, and the supernatant was centrifuged at 17,000 g for 30 min. Protein concentration was determined using Coomassie reagent. Samples were solubilized in Laemmli buffer containing 0.5% lithium dodecyl sulfate and run on a denaturing NUPAGE 4–12% Bis-Tris mini-gel using the MOPS buffer system (Invitrogen). Proteins were transferred to polyvinylidene difluoride plus nylon membranes by electroelution. Blots were incubated overnight at 4°C with primary antibody and then incubated with 1:2,000 horseradish peroxidase-conjugated donkey anti-rabbit IgG for 1 h (GE Healthcare, Piscataway, NJ). Antibody binding was visualized using the enhanced chemiluminescence system (Amersham International, Little Chalfont, UK). Primary antibodies utilized were 1:5,000 rabbit anti-mouse COX-1, 1:5,000 rabbit anti-mouse COX-2 (catalog nos. 160109 and 1601269, respectively; both from Cayman Chemicals), and 1:10,000 rabbit anti-human β-actin (Abcam, Cambridge, MA). All blots were reprobed for β-actin.

Real-time PCR. IMCD from CD ET-1 KO and control mice were isolated as described above. Total RNA was prepared using RNeasy minicolumns with on-column DNase I treatment (Qiagen, Valencia, CA). Samples were reverse transcribed, and real-time PCR was performed using a SmartCycler (Cephid, Sunnyvale, CA). Primer sequences for mouse COX-1 cDNA were forward, 5'-CAC TGG TGG ATG CCT TCT CT-3' and reverse, 5'-CCG TAC AGC TCC TCC AAC TC-3', which yielded a product size of 226 bp and amplified between bp 1405 and 1631 (GenBank NM_008969). Primer sequences for COX-2 cDNA were forward, 5'-CCC TGA AGC CGT ACA CAT CA-3' and reverse, 5'-TGT CAC TGT AGA GGG CTT TCA ATT-3', which yielded a product size of 80 bp and amplified between bp 1470 and 1550 (GenBank NM_011198). The primers for GAPDH were forward, 5'-TGG CCT CCA AGG AGT AAG AA-3' and reverse, 5'-CTG GGA TGG AAA TTG TGA GG-3', which yielded a product size of 110 bp. The ratio of COX-1 or COX-2 to GAPDH cDNA was determined for each sample.

Cyclic AMP studies. CD ET-1 KO and control mice were given 2 days of a normal Na diet and then killed. IMCD were prepared as described above; all incubations were done in Krebs buffer. IMCD were preincubated with vehicle alone, 10 µM indomethacin, or 25 µM NS-398 as described above, rinsed, and then incubated with 10 nM AVP with vehicle alone or with COX inhibitors at 37°C. Cells were extracted with ethanol, and cAMP was measured using ELISA (Assay Design, Ann Arbor, MI) using a SpectraMax Plus microplate spectrophotometer (Molecular Devices, Sunnyvale, CA). Total cell protein was measured using the Bradford assay. Cyclic AMP levels were normalized to total cell protein.

Statistics. Comparisons between floxed ET-1 and CD ET-1 KO mice were analyzed using one-way analysis of variance with Bonferroni correction. P < 0.05 was considered significant. Data are means ± SE.

	RESULTS

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CD ET-1 KO and control mice were analyzed at 3–4 mo of age. There were no differences between the two groups with respect to body weight or sex distribution (males = females within groups). On a normal Na diet, urinary PGE₂ excretion was significantly elevated in CD ET-1 KO animals compared with controls (Fig. 1). In mice placed on a high-Na diet for 3 days, urinary PGE₂ excretion markedly increased in both groups compared with a normal Na diet. However, in mice on a high-Na diet, urinary PGE₂ excretion remained greater in CD ET-1 KO mice compared with controls. The 3-day high-Na diet time period was based on the time at which maximal Na retention was observed in CD ET-1 KO mice after the change to a high Na intake (1). To determine the mechanism by which urinary PGE₂ is elevated in CD ET-1 KO mice compared with controls, we determined inner medullary COX-1 and COX-2 protein levels (Table 1). COX-1 protein expression was not detectably different between CD ET-1 KO and control mice maintained on a normal Na diet; furthermore, COX-1 protein expression was unchanged in either group by 3 days of a high-Na diet. COX-2 protein expression was also not different between CD ET-1 KO and control mice on a normal Na diet; 3 days of high Na intake increased COX-2 protein levels, but these were not different between CD ET-1 KO and control animals. Since failure to detect a difference in inner medullary COX protein expression could relate to the presence of non-CD cells, acutely isolated IMCD were studied. Despite combining inner medulla from five mice, COX-1 and COX-2 protein could not be detected in isolated IMCD. Consequently, COX-1 and COX-2 mRNA steady-state levels were determined in acutely isolated IMCD (Table 1). No differences in IMCD COX-1 mRNA levels were detected between CD ET-1 KO and control mice on a normal or high-Na diet; similarly, IMCD COX-2 mRNA levels were not different between CD ET-1 KO and control mice on either Na intake. Since mRNA levels do not necessarily reflect protein expression or enzyme activity, production of PGE₂ by acutely isolated IMCD and the effect of specific COX isoform inhibition were assessed. PGE₂ production was significantly increased in IMCD from CD ET-1 KO mice compared with controls when both groups had been maintained on a normal Na diet (Fig. 2). PGE₂ production was also higher in IMCD from CD ET-1 KO compared with control mice after both groups had been given 3 days of high Na intake (Fig. 2). Similar to the urinary PGE₂ excretion data, high Na intake increased IMCD PGE₂ production (compared with a normal Na diet) in IMCD from both groups of animals. NS-398, a specific COX-2 inhibitor, abolished PGE₂ production by IMCD from both groups to an extent comparable to that seen with indomethacin, thereby strongly supporting the notion that the elevated PGE₂ production in CDs from CD ET-1 KO mice is COX-2 dependent.

View larger version (8K): [in this window] [in a new window]   Fig. 1. Urinary PGE2 excretion in control and collecting duct (CD) endothelin-1 (ET-1) knockout (KO) mice. Values are shown after 2 days on a normal Na diet and after 3 days on a high-Na diet (n = 6 for each data point). *P < 0.025 vs. control animals on a similar Na diet. #P < 0.001 vs. same genotype on a normal Na diet.

View larger version (9K): [in this window] [in a new window]   Fig. 2. PGE2 production by inner medullary collecting duct (IMCD) acutely isolated from control and CD ET-1 KO mice previously treated with 2 days of a normal Na diet or 3 days of a high-Na diet. Cells were treated for 30 min with vehicle alone, a cyclooxygenase-2 (COX-2)-specific inhibitor (NS-398; 25 µM), or indomethacin (10 µM; Indo), followed by measurement of PGE2 release over the next 30 min (n = 12 for each data point). *P < 0.025 vs. control animals on a similar Na diet. #P < 0.001 vs. same genotype on a normal Na diet. $P < 0.001 vs. vehicle alone in same genotype and on same Na diet.

View larger version (12K): [in this window] [in a new window]   Fig. 3. Urine osmolality (A and B) and volume (C and D) in control and CD ET-1 KO mice on a normal Na diet and treated for 3 days with vehicle alone, Indo (5 mg·kg–1·day–1 ip; A and C) or NS-398 (10 mg·kg–1·day–1 ip; B and D) (n = 6 for each data point). *P < 0.01 vs. control treated with same COX inhibitor and vs. CD ET-1 KO treated with vehicle alone. **P < 0.025 vs. control treated with same COX inhibitor and vs. CD ET-1 KO treated with vehicle alone.

View larger version (12K): [in this window] [in a new window]   Fig. 4. Vasopressin (AVP)-stimulated cAMP accumulation in acutely isolated IMCD from control and CD ET-1 KO mice. Cells were treated for 30 min with vehicle alone, the COX-2-specific inhibitor NS-398 (25 µM), or Indo (10 µM), followed by addition of 10 nM AVP for 10 min (n = 6 for each data point). *P < 0.05 vs. control animals treated with same agents. #P < 0.001 vs. same genotype treated with AVP and vehicle alone.

View larger version (13K): [in this window] [in a new window]   Fig. 5. Systolic blood pressure (BP) in control and CD ET-1 KO mice. Animals were initially given (days 1 and 2) a normal Na diet. Indo (5 mg·kg–1·day–1 ip; A) or NS-398 (15 mg·kg–1·day–1 ip; B) was started on day 3 and continued after animals were changed to a high-Na diet on day 6 (n = 12 for each data point). *P < 0.001; **P < 0.01 vs. control animals on same day. #P < 0.05 vs. same COX inhibitor and normal Na diet in same genotype.

	DISCUSSION

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Although changes in COX-1 and COX-2 protein and mRNA expression in CD ET-1 KO mice could not be detected, the current study suggests that the apparent compensatory elevation in IMCD PGE₂ production in CD ET-1 KO mice is COX-2 dependent. This conclusion is supported by the findings that NS-398 caused similar increases in IMCD PGE₂ production and AVP-induced cAMP accumulation compared with indomethacin, whereas NS-398 reduced water excretion to an extent comparable to indomethacin (see below). The biological significance of COX-2 in the CD is uncertain. COX-2 mRNA has been localized to mouse IMCD, although COX-1 mRNA levels are relatively greater (11). In addition, acutely isolated rat IMCD PGE₂ production was more extensively inhibited by COX-2 than COX-1 blockade (10). COX-2 regulation of CD water transport has not been extensively investigated. In one study, bilateral ureteral obstruction increased COX-2 and decreased AQP2 protein expression in rat inner medulla; administration of NS-398 ameliorated the fall in AQP2 levels (3). Taken together, these studies support the notion that CD COX-2 may regulate water transport and that elevated COX-2-derived PGE₂ may help counterbalance the antidiuretic effect associated with ET-1 deficiency in the CD. These studies do not prove that increased COX-2 per se is responsible for the compensatory elevation in PGE₂ seen in CD ET-1 KO mice (changes in PGE₂ synthase or prostaglandin receptors could be involved); rather, these studies show that the increase in PGE₂ is through pathways that depend on COX-2.

The mechanisms by which increased CD PGE₂ might ameliorate the relative antidiuretic effect of CD ET-1 KO are speculative. Our group has previously reported that AVP-induced cAMP accumulation, in the presence of phosphodiesterase inhibition, is augmented in IMCD from CD ET-1 KO animals (4). The current study demonstrates that such increased AVP responsiveness is not abolished by complete blockade of PGE₂ production. Notably, blockade of PGE₂ production markedly increased cAMP levels, confirming that PGE₂ can reduce cAMP content in IMCD. Furthermore, these studies were done, for the first time, in the absence of phosphodiesterase inhibition, to help exclude a potential effect on cAMP phosphodiesterase activity. Taken together, the current data suggest that the elevated IMCD PGE₂ content in CD ET-1 KO mice likely impacts AVP-dependent water reabsorption at a point beyond regulation of cAMP levels. Such a finding is consistent with previous studies demonstrating that PGE₂ may reduce cell surface AQP2 expression by stimulating retrieval from the plasma membrane (13).

PGE₂, particularly in the renal medulla, has been shown to regulate BP; medullary infusions of COX-1 or COX-2 inhibitors in rats increase systemic BP (11). It is interesting, therefore, that inhibition of PGE₂ formation, whether nonspecifically with indomethacin or through COX-2 inhibition, while raising BP in both groups of mice, did not result in a greater elevation in BP in CD ET-1 KO mice compared with controls. The reasons for this are speculative, however, one possibility is that the regulation of BP is more dependent on medullary interstitial cell, as opposed to CD, PGE₂ production. Although it was not possible to examine, the increase in PGE₂ levels seen in CD ET-1 KO mice may conceivably reflect CD, but not interstitial cell, PGE₂ production. Interstitial cells produce and express relatively large amounts of PGE₂ and COX isoenzymes, respectively (2), and have been implicated in control of systemic BP (reviewed in Ref. 14). Clearly, this is an area in need of further investigation.

In summary, although ET-1 can stimulate IMCD PGE₂ production, the current study demonstrates that CD-derived ET-1 is not the primary determinant of CD PGE₂ synthesis. Furthermore, elevated COX-2-dependent CD PGE₂ production apparently partially compensates for the antidiuretic effect of CD ET-1 KO. This apparent compensation is likely mediated by a PGE₂ effect distal to AVP-stimulated cAMP accumulation. Thus the diuretic, natriuretic, and hypotensive effects of CD-derived ET-1 are mediated by other pathways.

	GRANTS

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This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases 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, 900 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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This Article Abstract Full Text (PDF) All Versions of this Article: 293/6/F1805    most recent 00307.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Kohan, D. E. Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Kohan, D. E.