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(Hypertension. 2000;36:395.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Dopamine₁ Receptor, G_s, and Na⁺-H⁺ Exchanger Interactions in the Kidney in Hypertension

Jing Xu; Xiao Xi Li; Frederick E. Albrecht; Ulrich Hopfer; Robert M. Carey; Pedro A. Jose

From the Departments of Pediatrics (J.X., X.X.L., F.E.A., P.A.J.) and Physiology and Biophysics (F.E.A., P.A.J.), Georgetown University Medical Center, Washington, DC; Department of Physiology, Case Western Reserve School of Medicine, Cleveland, Ohio (U.H.); and Department of Medicine, University of Virginia Health Sciences Center, Charlottesville (R.M.C.).

Correspondence to Pedro A. Jose, MD, PhD, Department of Pediatrics, Georgetown University Medical Center, 3800 Reservoir Rd NW, Washington, DC 20007. E-mail josep{at}gunet.georgetown.edu

	Abstract

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Abstract—The ability of dopamine₁ (D₁) receptors to inhibit luminal Na⁺-H⁺ exchanger (NHE) activity in renal proximal tubules and induce a natriuresis is impaired in spontaneously hypertensive rats (SHR). However, it is not clear whether the defect is at the level of the D₁ receptor, G_s, or effector proteins. The coupling of the D₁ receptor to G_s and NHE3 was studied in renal brush border membranes (BBM), devoid of cytoplasmic second messengers. D₁ receptor, G_s, and NHE3 expressions were similar in SHR and their normotensive controls, Wistar-Kyoto rats (WKY). Guanosine-5'-O-(3-thiotriphosphate) (GTPS) decreased NHE activity and increased NHE3 linked with G_s similarly in WKY and SHR, indicating normal G_s and NHE3 regulation in SHR. However, D₁ agonists increased NHE3 linked with G_s in WKY but not in SHR, and the inhibitory effects of D₁ agonists on NHE activity were less in SHR than in WKY. Moreover, GTPS enhanced the inhibitory effect of D₁ agonist on NHE activity in WKY but not in SHR, suggesting an uncoupling of the D₁ receptor from G_s/NHE3 in SHR. Similar results were obtained with the use of immortalized renal proximal tubule cells from WKY and SHR. We conclude that the defective D₁ receptor function in renal proximal tubules in SHR is proximal to G_s/effectors and presumably at the receptor level. The mechanism(s) responsible for the uncoupling of the D₁ receptor from G proteins remains to be determined. Because the primary structure of the D₁ receptor is not different between normotensive and hypertensive rats, differences in D₁ receptor posttranslational modification are possible.

Key Words: dopamine • receptors, dopamine • G protein • rats, inbred SHR

	Introduction

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Renal dopamine production, dopamine receptors, and dopamine receptor regulation are important in the pathogenesis of hypertension.¹ Dopamine, produced by renal proximal tubules, is an important paracrine/autocrine inhibitor of renal sodium transport under conditions of sodium loading.¹ The inhibition of sodium transport in renal proximal tubules by dopamine is exerted via the Na⁺-H⁺ exchanger (NHE) at the luminal or brush border membrane (BBM) and via Na⁺,K⁺-ATPase at the basolateral membrane.¹ The major transport of sodium across the luminal membrane of renal proximal tubules is caused by NHE activity.² Five of the 6 isoforms of NHE are expressed in the kidney.^{3 4} However, the NHE3 isoform predominates in the BBM of rat renal proximal tubules.^{2 5} There is an impaired ability of dopamine₁ (D₁₎-like receptors to inhibit NHE activity in BBM of the spontaneously hypertensive rat (SHR).¹ The decreased inhibitory effect of D₁-like receptors on NHE activity in renal proximal tubules and failure to induce a natriuresis cosegregate with hypertension in SHR and normotensive Wistar-Kyoto rat (WKY) crossbreeds.⁶ However, it is not clear whether the impaired inhibitory action of D₁-like receptors on NHE activity is at the receptors, G proteins, signal transducers, or effectors. G proteins can regulate NHE activity in renal BBM,⁷ and there are reports of decreased expression and activity of G_s,^{8 9} increased expression and activity of G_i,⁸ and increased activity of NHE in renal proximal tubules in SHR.^{10 11} We therefore designed experiments to determine the regulation of NHE activity in renal BBM by D₁-like receptors, via G_s, independent of cytoplasmic second messengers in WKY and SHR. However, a decreased generation of cAMP by D₁-like receptors^{12 13} contributes to the decreased ability of D₁-like agonist to inhibit NHE activity in renal proximal tubules in SHR.^{1 12} Moreover, post-cAMP sodium transport defect may develop with the establishment of hypertension.¹² Therefore, in additional studies, we determined the coupling of D₁-like receptors, G_s, and NHE3 in immortalized renal proximal tubule cells (PTC) from WKY and SHR.¹⁴

	Methods

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Preparation of BBM
Male WKY and SHR (Taconic Farms, Germantown, NY) were anesthetized with pentobarbital (50 mg/kg body wt IP). The mean arterial pressures were greater in SHR (>160 mm Hg) than in WKY (<100 mm Hg). The kidneys were harvested and the cortex was separated from the medulla before the animals were killed with an injection of pentobarbital (100 mg/kg body wt IV). Renal BBM were prepared by MnCl₂ precipitation and differential centrifugation as previously described.^{6 7 12}

Cell Culture
Immortalized renal PTC from microdissected S1 segments of proximal tubules from WKY and SHR were cultured in DMEM/F-12 with pyridoxine HCl, L-glutamine, and HEPES (15 mmol/L) buffer plus penicillin (100 U/mL), streptomycin (100 mg/mL), transferrin (5 µg/mL), insulin (5 µg/mL), epidermal growth factor (10 ng/mL), dexamethasone (4 µg/mL), fetal bovine serum 5%, and NaHCO₃ (7 mmol/L) on a 100-mm Petri dish.¹⁴

Measurement of NHE Activity
NHE activity was determined by the 100 µmol/L 5-(N-methyl-N-isobutyl)-amiloride–sensitive uptake of ²²Na⁺ at room temperature by rapid filtration technique with the use of 0.65-µm nitrocellulose filters.^{6 7 12} The BBM vesicles (BBMV) were preincubated with the indicated drugs for 30 minutes. Since amiloride-sensitive ²²Na⁺ uptake at 3 seconds is due mainly to NHE activity, comparisons were made at this time.^{6 7 12 15} Uptake of ²²Na⁺ at 1 to 2 hours was assumed to represent equilibrium values and also served as an index of vesicle size.^{6 7 12 15} Incubation of the BBM with drug or antibodies, which required access into the interior of the vesicle, was added during vesicle formation.^{6 7 12 15}

Immunoprecipitation Studies
BBM and immortalized PTC were incubated with vehicle or a D₁-like agonist (fenoldopam, 5x10^-6 mol/L) for 10 minutes and guanosine-5'-O-(2-thiodiphosphate) (GDPßS) (3x10^-4 mol/L), guanosine-5'-O-(3-thiotriphosphate) (GTPS) (3x10^-4 mol/L), or vehicle for 30 minutes. The membranes were lysed with ice-cold lysis buffer (PBS with 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 1 mmol/L EDTA, 1 mmol/L EGTA, 1 mmol/L sodium vanadate, 1 mmol/L PMSF, 10 µg/mL aprotinin, and 10 µg/mL leupeptin) for 1 hour and centrifuged at 14 000 rpm for 30 minutes. The lysates (supernatant) were then incubated with affinity purified anti-NHE3 antibody or anti-G_s antiserum (NEN) at 4°C for 1 hour and protein-A agarose at 4°C for 2 to 12 hours. The immunoprecipitates were pelleted and washed with lysis buffer (x4). After the sample buffer was added, the samples were boiled for 10 minutes and subjected to immunoblotting.

Immunoblotting Studies
The proteins were separated by electrophoresis (7.5% or 15% SDS–polyacrylamide gel) and then electrophoretically transferred onto nitrocellulose membranes. The trans-blots were probed with the indicated antibodies, detected by horseradish peroxidase–conjugated secondary antibody and an enhanced chemiluminescence system (Amersham Life). The densities of the appropriate bands were determined with the use of Quantiscan (Biosoft).¹⁶

Materials
Rabbit polyclonal anti-NHE3 and anti-D₁ receptor antibodies were produced against a synthetic oligopeptide from the amino acid sequence of rat NHE3 (amino acids 633 to 646)¹⁷ or rat D₁ receptor (amino acids 299 to 307) (Research Genetics). The antisera were affinity purified with immunizing peptide or protein A sepharose (Pharmacia). The antibodies are specific to their respective proteins determined by Western blotting with preimmune sera or preadsorbed antibody and immunoprecipitation.^{17 18}

Other materials included the following: GTPS and GDPßS (Calbiochem); 5-(N-methyl-N-isobutyl)-amiloride, 5-(N-ethyl-N-isopropyl)-amiloride, dopamine, and SKF81297 (Research Biochemicals); fenoldopam (Smith Kline Beecham); and G protein subunit antibodies (NEN Life Science Products). All other reagents were from Sigma Chemical Co.

Statistical Analysis
Data are expressed as mean±SE. Differences within groups were analyzed by ANOVA for repeated measures, followed by Scheffé’s test; the paired t test was used when only 2 groups were compared. Differences among groups were analyzed by 1-way ANOVA, followed by Duncan’s or Scheffé’s test.

	Results

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D₁ Receptors, G_s, G_i, and NHE3 Are Expressed in Renal BBM
The expressions of D₁ receptors, G_s, G_i, and NHE3 in BBM and immortalized PTCs were similar in WKY and SHR (Figure 1). Although there are 2 D₁-like receptors (D₁ and D₅), D₁ receptor function seems to predominate over the D₅ receptor^{1 6} ; thus, only the D₁ receptor was studied in these experiments.

View larger version (34K): [in this window] [in a new window]   Figure 1. Expression of NHE3, D1 receptor, Gs, and Gi in BBM and immortalized PTC. BBM (top) and immortalized PTC (bottom) from WKY and SHR were immunoblotted with antibodies against NHE3, D1 receptor, Gs, and Gi. The expressions of NHE3, D1 receptor, Gs, and Gi were similar in WKY and SHR (t test). Representative immunoblots are depicted on top of the bar graphs.

Dopamine and D₁-Like Agonists Inhibit NHE Activity in WKY to a Greater Extent Than in SHR
In BBMV, a system devoid of cytoplasmic components and second messenger, basal NHE activity was slightly but not significantly greater in SHR (3.0±0.7 nmol Na per milligram protein per minute; n=11) than in WKY (2.1±0.3; n=12) (P>0.05, t test). Dopamine and the D₁-like agonists fenoldopam and SKF81297 inhibited NHE activity to a greater extent in WKY than in SHR (Table ). In a separate group of studies, the effect of varying concentrations of SKF81297 (5x10^-8 to 5x10^-5 mol/L; 4 concentrations; n=5 to 7/concentration) on NHE activity was determined. The maximum effect (calculated from Lineweaver-Burk plots) was slightly greater but not significantly different in WKY than in SHR (42±12% versus 35±10%, respectively; P>0.05, t test). However, the concentration that produced a half-maximal effect was significantly less in WKY than in SHR (57±31 versus 388±28 nmol/L, respectively; P<0.05, t test). We have reported that the ability of fenoldopam to inhibit NHE activity in BBMV is blocked by D₁-like antagonists, indicating action at D₁-like receptors.⁷

View this table: [in this window] [in a new window]   Table 1. Percent Inhibition From Control of NHE Activity in BBMV by Dopamine and D1 Agonists

GTPS Inhibits NHE Activity in Both WKY and SHR
The decreased inhibitory effect of fenoldopam on NHE activity in SHR was not due to impaired G_s function, because the nonhydrolyzable GTP analogue GTPS inhibited the NHE activity in BBMV to a similar extent in adult WKY and SHR (Figure 2). However, GTPS increased the inhibitory effect of fenoldopam (5x10^-6 mol/L) on NHE activity in WKY (33.2±14.1%; n=5; P<0.05 versus fenoldopam alone) but not in SHR (6.9±5.67%; n=12; P>0.05 versus fenoldopam alone), indicating impaired coupling between D₁-like receptors and G_s in SHR. The effect of GTP on NHE activity was specific because ATPS had no effect on NHE activity in either WKY or SHR (data not shown).

View larger version (16K): [in this window] [in a new window]   Figure 2. Effect of GTPS on NHE activity in BBMV. Vehicle or GTPS was introduced inside BBMV from WKY and SHR and allowed to incubate for 30 minutes. *P<0.05, ANOVA for repeated measures, Scheffé’s test, vs control (0) in both WKY and SHR.

Fenoldopam Increases the Amount of NHE3 Coimmunoprecipitated With G_s in WKY but not in SHR
Because the inhibitory effect of G proteins on NHE activity in BBM is exerted mainly by G_s,¹⁹ we studied the interaction between D₁-like receptors and G_s. Under basal conditions, more G_s was bound to NHE3 in immortalized PTC in SHR than in WKY. Fenoldopam (5x10^-6 mol/L) increased NHE3 coimmunoprecipitated with G_s in BBM and immortalized PTC in WKY but not in SHR (Figure 3). However, GTPS, but not GDPßS, increased NHE3 coimmunoprecipitated with G_s in both WKY and SHR (Figure 4), indicating normal coupling between G_s and NHE3.

View larger version (27K): [in this window] [in a new window]   Figure 3. Effect of the D1-like agonist fenoldopam on NHE3 and Gs in BBMV and immortalized PTC. After BBMV (top) or immortalized PTC (bottom) were incubated with vehicle (control) or fenoldopam (5 µmol/L) for 10 minutes, the samples were immunoprecipitated with anti-Gs antibodies and immunoblotted with anti-NHE3 antibodies. *P<0.05 vs control WKY, #P<0.05, SHR vs WKY, ANOVA, Scheffé’s test. Representative immunoblots are depicted on top of the bar graphs.

View larger version (34K): [in this window] [in a new window]   Figure 4. Effect of GTPS on NHE3 and Gs in BBMV and immortalized PTC. The BBMV (top) or the membranes of immortalized PTC (bottom) were incubated with vehicle (control), GTPS (3x10-4 mol/L), and GDPßS (3x10-4 mol/L) for 30 minutes. Thereafter, the samples were immunoprecipitated with anti-NHE3 antibodies and immunoblotted with anti-Gs antibodies in BBMV. In immortalized PTC, the samples were immunoprecipitated with anti-Gs antibodies and immunoblotted with anti-NHE3 antibodies. *P<0.05, ANOVA followed by Duncan’s or Scheffé’s test. Representative immunoblots are depicted on top of the bar graphs.

	Discussion

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These studies confirm previous reports that dopamine and D₁-like agonists inhibit NHE activity in renal brush border to a lesser extent in hypertensive than in normotensive rats.^{6 12} Two D₁-like receptors, D₁ and D₅, are expressed in BBM; however, D₁ receptor function seems to predominate over D₅ receptor function.^{1 6} We now report that the decreased D₁-like action in BBM in hypertension is not due to decreased expression of D₁ receptors in renal BBM. Previous reports have also found that the expression of D₁-like receptors (determined by radioligand binding) is not different in renal proximal tubules in WKY and SHR.^{12 20} However, the D₁ receptor in renal proximal tubules is expressed to a greater extent in cytosol than in surface membranes.¹⁸ A comparison of D₁ expression in BBM of WKY and SHR has not been reported; NHE3 is expressed at BBM and is responsible for the majority of sodium transport into the proximal tubule.^{2 4 5} NHE activity in renal proximal tubules has been reported not to be regulated in hypertensive rats.²¹ In genetically hypertensive rats, the inhibitory effects on renal proximal tubular NHE activity and natriuretic action of dopamine and D₁-agonists are impaired.^{22 23 24} NHE3 expression and activity have also been reported to be variably increased in renal proximal tubules of SHR^{6 11 25} ; the NHE isoform expressed in BBM of renal proximal tubules is NHE3.^{4 5} In the present study, NHE expression tended to be higher in SHR than in WKY in BBMV but not in immortalized PTC. However, NHE activity was not different between normotensive and hypertensive rats.

In the present study dopamine and 2 different D₁-like agonists (fenoldopam and SKF82917) had an attenuated inhibitory effect on NHE activity. The mechanism for the decreased ability of dopamine and D₁ agonists to inhibit NHE activity in renal proximal tubules in genetic hypertension has been related to decreased cAMP production following dopaminergic stimulation.^{1 6 12 20 23} However, in the present study, which used BBMV, D₁ agonists inhibited NHE activity via G_s, independent of cytoplasmic second messengers.⁷ GTPS inhibited NHE activity in BBMV to a similar extent in WKY and SHR. The ability of GTPS and cAMP to inhibit NHE activity to a similar degree in WKY and SHR¹² suggests that the impaired D₁-like action on NHE activity is caused by a defective coupling of D₁-like receptors with G_s. G proteins, which are composed of heterotrimer subunits G, G_ß, and G, are expressed in renal proximal tubules.^{9 26} G protein subunit abundance in kidneys of WKY and SHR has not been shown to be consistently different between these 2 rat strains.^{10 27} In the present study we find no differences in the abundance of G_s or G_i in BBM or immortalized PTC from WKY and SHR. NHE activity in BBMV can be inhibited by G_s and can be stimulated by G_i and Gß dimers.¹⁹ G_i does not influence D₁ action on NHE activity in BBMV in WKY.¹⁹ However, in renal proximal tubules of SHR, pertussis toxin normalized the inhibitory effect of dopamine on sodium pump activity.⁸ Increased G_i activity is probably not involved in the diminished inhibitory effect of D₁-like agonists because pertussis toxin did not affect the ability of fenoldopam to inhibit NHE activity (data not shown). Previous studies have shown that G_s can directly mediate the inhibitory effect of D₁ agonists and GTPS on NHE activity.¹⁹ In the present report the inhibition of NHE activity by GTPS in BBMV in WKY and SHR is associated with an increase in binding of G_s to NHE3 to a similar degree in both rat strains. In contrast, the D₁-like agonist fenoldopam increased the quantity of G_s bound to NHE3 in BBM of WKY but not in SHR. These studies support the notion that the failure of D₁ receptors to inhibit NHE3 activity in BBM is caused by an impaired coupling of the D₁ receptor to G_s and not caused by abnormalities in NHE3 or G_s per se.^{1 6 9 12 20 23} Although the other D₁-like receptor, the D₅ receptor, is also expressed in renal proximal tubules, its influence on renal tubular function is minimal relative to the D₁ receptor.^{6 28}

The difference in inhibition constant but not in maximum effect of SKF81297 and previous studies that showed similar maximum receptor density but a lower D₁-like agonist affinity in renal proximal tubules in SHR than in WKY support the concept of an inefficient coupling between D₁-like receptors and G_s in SHR.¹² The mechanism of the inefficient coupling of the D₁ receptor with G proteins in the kidney is not known. Increased renal and urinary dopamine levels in SHR could be taken to suggest homologous desensitization as a mechanism.^{1 29} In the present study we show that immortalized PTC from SHR carry a phenotype (D₁-like receptor function) similar to that of the native kidney. In immortalized PTC from SHR, fenoldopam also failed to increase NHE3 binding to G_s, but as in the native kidney, GTPS increased the quantity of G_s bound to NHE3 to a similar extent in WKY and SHR. Homologous desensitization cannot be invoked in these cells because exogenous L-dopa is necessary for renal PTC to synthesize dopamine.³⁰ It is not due to an abnormality in the primary structure of the D₁ receptor.³¹ However, abnormal posttranslational modification is possible.³¹ Thus, we have reported that the serine-phosphorylation of the D₁ receptor in renal proximal tubules is increased in SHR and in essential hypertension.^{1 31} G protein–coupled receptor kinases GRK2, GRK3, and GRK5 desensitize the D₁ receptor, in part, by serine-phosphorylation.³² GRK activity and GRK2 expression are increased in lymphocytes of patients with essential hypertension and in rats with genetic hypertension.^{33 34} The increase in GRK2 expression occurs after the establishment of hypertension.³⁴ However, hypertension seems to increase the activity and expression of GRK5 in rat aortic smooth muscles.³⁵ The ubiquitous expression of these G protein–coupled receptor kinases also does not explain the organ and nephron segment specificity of the uncoupling of the D₁ receptor in genetic hypertension.¹ We have suggested that the uncoupling of the D₁ receptor in genetic hypertension may be due to a kinase but not necessarily due to GRK2.^{31 36}

In conclusion, we have shown that in renal PTC and specifically in BBM, D₁ receptor, G_s, G_i, and NHE3 expressions are similar in WKY and SHR. GTPS inhibits NHE activity and increases binding of G_s and NHE3 to a similar extent in WKY and SHR. However, D₁-like agonist inhibition of NHE3 activity and increase of the binding of G_s and NHE3 are impaired in SHR compared with WKY. These studies suggest that a defective D₁ receptor/G_s coupling may be responsible, in part, for the defective inhibitory action of dopamine and D₁-like agonists on NHE activity in renal proximal tubular BBM.

	Acknowledgments

 
This work was supported in part by grants from the National Institutes of Health (DK39308, DK52612, and HL23081). We would also like to thank Dr Daniel Biemesderfer for NHE3 antibodies used in comparison with NHE3 antibodies produced by Research Genetics.

	Footnotes

 
December 20, 1999; first decision January 3, 2000; revision accepted April 11, 2000.

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