Published online before print January 2, 2008, doi: 10.1161/HYPERTENSIONAHA.107.100099
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(Hypertension. 2008;51:360.)
© 2008 American Heart Association, Inc.
Original Articles |
Differential D1 and D5 Receptor Regulation and Degradation of the Angiotensin Type 1 Receptor
From the Department of Pathology (J.J.G., X.W., R.A.F.), University of Virginia, Charlottesville; and the Department of Pediatrics (P.A.J.), Georgetown University Medical Center, Washington, DC.
Correspondence to Robin A. Felder, Department of Pathology, University of Virginia, PO Box 800403, Charlottesville, VA 22908. E-mail rfelder{at}virginia.edu
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Abstract |
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Renal sodium transport is increased by the angiotensin type 1 receptor (AT1R), which is counterregulated by dopamine via unknown mechanisms involving either the dopamine type 1 (D1R) or dopamine type 5 receptor (D5R) that belong to the D1-like receptor family of dopamine receptors. We hypothesize that the D1R and D5R differentially regulate AT1R protein expression and signaling, which may have important implications in the pathogenesis of essential hypertension. D1R and D5R share the same agonists and antagonists; therefore, the selective effects of either D1R or D5R stimulation on AT1R expression in human renal proximal tubule cells were determined using antisense oligonucleotides selective to either D1R or D5R. We also determined the role of receptor tyrosine kinase and the proteosome on the D1R/D5R-mediated effects on AT1R expression and internalization. In renal proximal tubule cells, D5R (not D1R) decreased AT1R expression (half-life: 0.47±0.18 hours) and AT1R-mediated extracellular signal–regulated kinase 1/2 phosphorylation (232±18.9 U with angiotensin II [10–7 mol/L] versus 81±8.9 U with angiotensin II [10–7 mol/L] and fenoldopam [D1R/D5R agonist; 10–6 mol/L; P<0.05; n=6). The fenoldopam-induced decrease in AT1R expression was reversed by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3,4-d) pyrimidine (c-Src tyrosine-kinase inhibitor) and clasto-lactacystin β-lactone (proteasome inhibitor), demonstrating that the fenoldopam-mediated decrease in total cell AT1R expression is a result of a c-Src- and proteasome-dependent process. D5R stimulation decreases AT1R expression and is c-Src and proteasome dependent. The discovery of differential regulation by D1R and D5R opens new avenues for the development of agonists selective to either receptor subtype as targeted antihypertensive agents that can decrease AT1R-mediated antinatriuresis.
Key Words: dopamine 1–like receptor • angiotensin type 1 receptor • human renal proximal tubular cells • D1 receptor • D5 receptor
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Introduction |
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The importance of abnormal renal sodium handling in the pathogenesis of hypertension and salt sensitivity has stimulated studies on the interaction between counterregulatory natriuretic pathways. Dopamine and angiotensin II stimulate 2 counterregulatory pathways through specific G protein–coupled receptors in the renal proximal tubule where the natriuretic effect of the dopamine type 1 (D1R) and dopamine type 5 receptors (D5R)1–6 and the antinatriuretic effect of the angiotensin type 1 receptor (AT1R)7 counterbalance each other to maintain sodium and blood pressure homeostasis.
The renal proximal tubule and thick-ascending limb of Henle are the sites of increased sodium reabsorption in human essential hypertension,8–10 which is regulated by dopamine1–5,9–12 and angiotensin II.7,9,10,13 Angiotensin II is responsible for >50% of sodium reabsorbed by the kidney under basal conditions,7,13,14 whereas dopamine is responsible for >50% of sodium excreted under conditions of sodium excess.1–5,12,15 Previous studies in normotensive rodents demonstrated that stimulation of both the D1R and D5R by D1-like receptor agonists (because of the lack of availability of pharmacological agents that are selective only to the D1R or the D5R) decreased AT1R protein expression but increased the expression of the D1R.16 In the spontaneously hypertensive rat, a rodent model of genetic hypertension and D1R and D5R stimulation also decreased AT1R, but not the D1R protein, in renal proximal tubular cells (RPTCs).16 Whether the D1R and/or the D5R regulate the AT1R in human RPTCs or the spontaneously hypertensive rat has not been directly determined.
The natriuretic effect of D1-like receptor stimulation is enhanced when the biosynthesis of angiotensin II is reduced or when the AT1R is blocked,17,18 suggesting that angiotensin II exerts a tonic control of the dopaminergic pathway. D1R can regulate AT1R function by direct receptor/receptor interaction,16,19 but a regulatory role of D5R on AT1R has not been demonstrated directly. The enhanced antinatriuretic effect of the renin-angiotensin system in genetic hypertension could be further exacerbated by the impaired counteractive natriuretic effect of the renal dopaminergic system.15 The mechanisms responsible for the counterregulation of the dopaminergic and AT1Rs under normal blood pressure conditions are not well understood.
Despite the fact that the D1R and D5R arise from different genes and exhibit 49% amino acid sequence homology, they have similar affinities toward dopaminergic agonists and antagonists.20–22 Therefore, to test our hypothesis that there is differential regulation of the AT1R by the D1R and D5R, we selectively silenced the D1R or D5R gene using antisense oligonucleotides selective to either D1R or D5R. In addition, we used human RPTC lines in which the D1Rs are uncoupled from intracellular signaling (D1R-uncoupled RPTC)23,24 to determine the selective D5R (in the absence of a functional D1R) effect on AT1R expression in these cells.
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Materials and Methods |
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Human RPTC Cultures
Human kidneys were obtained as fresh surgical specimens from patients who had unilateral nephrectomy because of renal carcinoma or trauma under a university institutional review board–approved protocol that included informed consent that adheres to the Declaration of Helsinki and the most recent version of Title 45, Part 46, US Code of Federal Regulations. Only the visually and histologically normal pole, distal from the affected part of the kidney, was used in our studies. All of the studies were performed in duplicate on 3 established lines of RPTCs. We have reported previously on the characteristics of these cell lines, including cell lines from hypertensive subjects with D1Rs that are uncoupled from G proteins and other effector proteins.23–25
RPTCs were grown at 37°C, 100% humidity, 95% air, and 5% CO2 and fed serum-free medium every 4 days consisting of a mixture of Click’s RPMI 1640 (Quality Biological Inc) supplemented with 5 µg/mL of insulin, 5 µg/mL of transferrin, 5 ng/mL of selenium, 36 ng/mL of hydrocortisone, 4 pg/mL of triiodothyronine, 10 ng/mL of epidermal growth factor (Sigma), 100 U/mL of penicillin G, and 100 µg/mL of streptomycin.23–25 Before reaching confluence, the cells were subcultured using trypsin-EDTA (0.025%; 0.01%), inactivating the trypsin with 5% serum, spun at 60g, and resuspended in serum-free growth medium for passaging. Cells were used at 70% to 80% confluence in 6-well culture plates between the first and fourth doublings, with experiments performed in duplicate in 3 cell lines.
Drug Treatment
Because highly selective D1R or D5R pharmacological agents do not yet exist, we used the most selective agonists and antagonists to both D1R and D5R (D1-like receptors) available. The cells were incubated for the indicated times with fenoldopam, an agonist selective to both D1R and D5R (Sigma) in the absence or presence of SCH-23390, an antagonist selective to both D1R and D5R (Sigma). When used, SCH-23390 was added 20 minutes before the addition of fenoldopam to block both the D1R and D5R. The drug incubations were terminated with 3 washes of Dulbecco’s PBS. 4-Amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3,4-d) pyrimidine (PP2), a specific Src nonreceptor tyrosine kinase inhibitor, was used at the 1 µmol/L concentration.26 Clasto-lactacystin β-lactone (CLBL), a highly specific cell-permeable proteasome inhibitor, was used at the 10 µmol/L concentration.27
Immunoblotting
Cells were homogenized in ice-cold lysis buffer (20 mmol/L of Tris-HCl [pH 7.4], 2 mmol/L of EDTA [pH 8.0], 2 mmol/L of EGTA, 100 mmol/L of NaCl, 10 µg/mL of leupeptin, 10 µg/mL of aprotinin, 2 mmol/L of phenylmethylsulfonyl fluoride, and 1% Nonidet P-40), sonicated, kept on ice for 1 hour, and centrifuged at 26 000g for 30 minutes. The supernatant represented crude cell membranes. Protein concentrations were determined by the BCA protein assay kit (Pierce Biotechnology), using BSA as a standard. The proteins, separated by SDS-polyacrylamide gel electrophoresis, were electrophoretically transferred onto polyvinylidene difluoride membranes (Bio-Rad Laboratories). Equal sample loading and transfer were determined by Ponceau S (Sigma) staining of the polyvinylidene fluoride membrane before immunodetection. Transblots were blocked with 5% nonfat dry milk in Dulbecco’s PBS with 0.05% Tween-20 and incubated with diluted affinity-purified rabbit polyclonal antibody to AT1R (1:400 dilution, sc-1173, Santa Cruz), D1R (1:200 dilution, sc-14001, Santa Cruz), D5R (1:500 dilution, sc-25650, Santa Cruz), phospho-extracellular signal–regulated kinase (ERK) 1 and 2, c-Src, and phosphor tyrosine Y416 c-Src (1:1000, Cell Signaling Inc) for 1.5 hours at room temperature. After 5 washes for 10 minutes each, the membranes were incubated with diluted peroxidase-labeled goat anti-rabbit IgG (Santa Cruz Biotechnology Inc) in 2% milk for 1.5 hours at room temperature and washed as for the primary antibody. The chemiluminescence signal was developed using SuperSignal West Pico substrate (Pierce Biotechnology) for AT1R and phospho-ERK 1 and 2; SuperSignal West Femto (Pierce Biotechnology) for D1R and D5R; and c-Src and was then exposed to x-ray film.
Cell Plasma Membrane Expression of AT1R
Cell-surface membrane sheets were isolated with a detergent-free isolation procedure using sulfo-NHS-SS-biotin.28 RPTCs, after a 20-minute incubation with the D1-like receptor agonist fenoldopam (10–6 mol/L), were washed twice with Hank’s balanced salt solution with magnesium and calcium and then labeled with 1 mmol/L of sulfo-NHS-SS-biotin for 10 minutes. The labeling compound was simultaneously washed and inactivated with 2 washes of Tris-buffered saline. The cells were then scraped off the plate in ice-cold detergent-free lysis buffer (Tris-buffered saline with protease inhibitors), sonicated for 1 second, incubated on ice with streptavidin beads (Ultralink, Pierce) for 20 minutes, washed twice with Tris-buffered saline, and eluted in gel loading buffer (NuPAGE LDS Sample Preparation Buffer with reducing agents, Invitrogen). Immunoblotting for AT1R protein was performed as described above.
Antisense Oligonucleotides
The effects of 50 nM of propyne/phosphorothioate-modified antisense oligonucleotides for human (h)D5R (5'- 136 nucleotide CAGCATTTCGGGCTGGAC 153 nucleotide -3'; GenBank accession No. M67439) and hD1R (5'-277 nucleotide GGTGTTCAGAGTCCTCAT 294 nucleotide-3'; GenBank accession No. X55760) were compared with scrambled sequence controls (hD5 5'-GTCGCCCGAGCTTATGGA-3' and hD1R 5'-GGGTACTCTCT ATATCGG-3'). Briefly, cells were grown in 6-well plates until 60% confluence, and 50 nM antisense or scrambled oligonucleotides were mixed with 6 µL of oligofectamine in Optimem medium (Invitrogen Life Technologies) and incubated for 24 hours, then switched to growth medium and incubated for an another 24 hours. Fenoldopam (10–6 mol/L) was then added to the medium without growth factors for 2 hours, lysed, and processed for immunoblotting for the D1R, D5R, and AT1R.
Statistical Analysis
The data are expressed as mean±SE. Comparisons within and among groups were made by repeated-measures or factorial ANOVA, respectively, followed by Holm-Sidak or Duncan’s test. A t test was used for 2-group comparisons. A P value of <0.05 was considered significant.
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Studies in RPTCs
Effect of D1R/D5R Stimulation on AT1R Expression
We compared AT1R responses to dopaminergic stimulation in human RPTCs with those reported previously in rodent cells using the D1R/D5R agonist fenoldopam. D1R/D5R stimulation decreased the expression of the AT1R in a time-dependent manner, as determined by immunoblotting (Figure 1). The half-life of the AT1R under these conditions (fenoldopam; 10–6 mol/L) was 0.47±0.18 hours, as determined by nonlinear regression analysis. This effect of fenoldopam (10–6 mol/L for 4 hours) was fully reversed by the use of the D1R/D5R antagonist SCH 23390 at a dose that, by itself, was determined previously not to have an effect on AT1R expression (10–7 mol/L; Figure 1, inset).
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Effect of D1R/D5R Stimulation on AT1 Function
To demonstrate that AT1R function was similarly downregulated by D1R/D5R stimulation in our human cell line, we studied a well-established measure of AT1R activity, namely, the angiotensin II–dependent phosphorylation of ERK1/2.29–31 RPTCs were incubated with fenoldopam (10–6 mol/L) or vehicle for 4 hours, stimulated with angiotensin II (10–7 mol/L) for 10 minutes, and immunoblotted for phospho-ERK1/2. Fenoldopam nearly completely inhibited the angiotensin II–dependent increase in phospho-ERK1/2 (Figure 2 and inset). To verify that the reduction in phospho-ERK1/2 was because of the reduction in AT1R expression and not because of a non-AT1R–mediated event or an alteration in postreceptor signaling, we studied ERK1/2 phosphorylation induced by epidermal growth factor. Epidermal growth factor (100 ng/mL) was able to equally induce phosphorylation of ERK1/2 in the presence or absence of fenoldopam (10–6 mol/L; Figure 2 and inset).
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To determine whether either the D1R or the D5R was responsible for the fenoldopam-induced decrease in AT1R expression, we used antisense oligonucleotides to reduce the expression of either D1R or D5R. RPTCs were incubated with D1R or D5R antisense or scrambled propyne/phosphorothioate oligonucleotides (5x10–8 mol/L) for 48 hours, and D1R and D5R proteins were quantified by immunoblotting (Figure 3). D1R expression was decreased by the D1R antisense but not by either D1R scrambled or D5R antisense or scrambled oligonucleotides (D1R antisense: 68.01±4.18% reduction compared with scrambled control; P<0.01; n=3). In contrast, D5R expression was decreased by D5R antisense but not by the D5R scrambled or D1R antisense or scrambled oligonucleotides (D5R antisense: 55.01±6.15% reduction compared with scrambled control; P<0.01; n=3). Similarly treated cells were then split into 2 wells and stimulated with fenoldopam (10–6 mol/L) or vehicle for 2 hours, lysed, and immunoblotted for the AT1R (Figure 4). In these cells, fenoldopam treatment for 2 hours again decreased AT1R protein expression (Figure 4A), albeit to a lesser extent relative to cells treated with fenoldopam for 4 hours but not with Optimem (Figure 1). D1R antisense and scrambled oligonucleotides had no significant effect on the fenoldopam-dependent decrease in AT1R protein (Figure 4B). In contrast, D5R antisense but not D5R scrambled oligonucleotides blocked the fenoldopam-dependent decrease in AT1R expression by 57.9±13.6% (n=3; P<0.001; Figure 4C). These studies suggest that D5R but not D1R mediates the inhibitory effect of fenoldopam on AT1R protein expression. The increase in AT1R protein in cells not exposed to fenoldopam but treated with D5R antisense oligonucleotides supports the notion that D5R is constitutively active.32
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Because the fenoldopam-mediated decrease in AT1R expression occurred too fast to be accounted for by alterations in transcription and translation (half-life: 0.47±0.18 hours), we determined whether the action may have occurred by enhancement of its degradation. In HEK-293 cells heterologously expressing the AT1R and D5R, pulse chase experiments with protein translation inhibited by cycloheximide showed that fenoldopam promoted AT1R degradation via the proteasome.33 Because protein degradation in the proteasome can be triggered by c-Src tyrosine kinase,26 we studied the effect of fenoldopam (10–6 mol/L) on AT1R expression in cells treated with PP2, a c-Src nonreceptor tyrosine kinase inhibitor, or CLBL (a proteasome inhibitor).27 As shown in Figure 5, either PP2 or CLBL completely blocked the fenoldopam (10–6 mol/L for 4 hours)-mediated decrease in AT1R expression. We selected concentrations of PP2 and CLBL that, by themselves, had no significant effect on AT1R expression; high concentrations of PP2 and CLBL by themselves caused an increase in AT1R expression (data not shown). Presumably, the effect of fenoldopam was exerted via c-Src, because fenoldopam increased c-Src tyrosine phosphorylation at the Y416 site by 2.7±0.4-fold over the control group (vehicle-treated cells), and this increase was completely blocked by the c-Src tyrosine kinase inhibitor PP2 (Figure 6).
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Studies in RPTCs With Uncoupled D1Rs
To determine the effect of D5R stimulation on AT1R expression in the absence of functional D1R (D1R uncoupled),23–25 we measured the effect of fenoldopam (10–6 mol/L) on AT1R expression in both normal human RPTCs and RPTCs with uncoupled D1Rs (uncoupled RPTCs). A 4-hour fenoldopam stimulation produced a similar concentration-dependent decrease in AT1R expression in both RPTCs and uncoupled RPTCs, as determined by immunoblotting (Figure 7). As determined by nonlinear regression analysis, the half-maximal concentrations of fenoldopam were similar in normal RPTCs (24.6 nM) as compared with D1R uncoupled RPTCs (15.8 nM; n=6 per concentration; P>0.05). The congruence of the results (with those described in Figure 4) suggests that the D5R-mediated decrease in AT1R expression is not because of an 
-error.
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Studies in Surface Labeling of AT1R
AT1R was reduced in our whole-cell preparations. However, we wished to determine whether cell surface expression was reduced, because cell surface receptors are most likely be the receptors that are responsive to angiotensin II. Membrane localization of AT1R under identical experimental protocols described for Figure 7 demonstrated that fenoldopam (10–6mol/L per 20 minutes) reduced the control membrane expression from 58 888±1667 relative fluorescent units to 32 224±4250 relative fluorescent units (n=6; P<0.05; Figure S1). The magnitude of the decrease in cell surface expression of AT1R induced by a 20-minute incubation with fenoldopam is similar to the decrease in total cellular AT1R expression (Figure 1). These studies indicate that fenoldopam not only can decrease total cellular expression of AT1R but also AT1R expression at the plasma membrane. AT1R degradation induced by fenoldopam starts at the plasma membrane in HEK 293 cells heterologously expressing human AT1R and human D5R but not human D1R.33
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Discussion |
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The current study in human RPTCs confirms our previous studies in rodent RPTCs where we demonstrated that simultaneous D1R and D5R stimulation results in a decrease in the expression of the AT1R protein.16 The current studies extend these earlier findings by demonstrating in human RPTCs that the D5R is responsible for AT1R downregulation. We conducted our studies in 6 human RPTC lines, 3 derived from normal subjects (with no significant medical history of hypertension) and 3 that have demonstrated a coupling defect between the D1R and adenylyl cyclase activity, termed "D1R uncoupled RPTCs,"23–25 similar to those noted in RPTCs from spontaneously hypertensive rats.34
The D1-like receptor is natriuretic,1–5,12,15 whereas the AT1R is antinatriuretic7,13,14,35; thus, a downregulation of AT1R expression and function by the D1R and/or D5R should amplify the natriuretic effect of D1-like receptor stimulation. Indeed, in normotensive rats and dogs, the natriuretic effect of the D1-like agonist fenoldopam is enhanced in the presence of inhibition of angiotensin II synthesis or AT1R blockade.17,18 There is impairment of the ability of the D1-like receptor agonist fenoldopam to inhibit renal proximal tubule sodium transport in humans with salt-sensitive essential hypertension or to induce a natriuresis in rodent models of essential hypertension.1–5,23,36–38 The relative contributions of D1R and D5R to the sodium retention in human essential hypertension and rodent models of genetic hypertension remain to be tested.
The ability of D5R to decrease AT1R expression in vitro may have a physiological consequence in vivo. D5R-deficient mice are hypertensive because of renal and nonrenal mechanisms. The acute regulation of the high blood pressure in D5R-deficient mice seems to be mediated by a central nervous system mechanism involving the 1-adrenergic pathway.39 However, chronic administration of the AT1R antagonist losartan decreases blood pressure to a greater extent in D5R-deficient mice than their wild-type littermates (Dr Pedro A. Jose, unpublished data, 2007). Although the D5R action (inhibition of AT1R expression) persists in RPTCs from genetically hypertensive rodents, renal D5R expression is decreased.40 Therefore, the impaired D1-like receptor inhibition of sodium transport in hypertension may be secondary to impairment of both D1R and D5R (function and/or expression), at least in rodents. Indeed, disruption of either the D1R or D5R gene in mice results in hypertension.39,41
The D5R-mediated AT1R downregulation occurs in 30 minutes, too fast for transcriptional-based protein downregulation of AT1R protein expression in the human renal proximal tubule (Dr Pedro A. Jose, unpublished data, 2007). In HEK-293 cells heterologously expressing the AT1R and D5R but not D1R, pulse chase experiments, with protein translation inhibited by cycloheximide, show that fenoldopam also decreases AT1R expression with a half-life of 37.7 minutes, close33 to the half-life of 28.2 minutes observed in the current report. The process must be related to increased degradation, because the D5R-mediated reduction of AT1R is completely blocked by an inhibitor of proteasome activity. There are examples of protein-linked proteasome- and c-Src tyrosine kinase–mediated protein degradation,26 suggesting that a similar pathway may be active in AT1R downregulation. In fact, we demonstrate that fenoldopam mediates the decrease in total cell AT1R expression as a result of a c-Src- and proteasome-dependent process. c-Src, when tyrosine phosphorylated at Y416 in the activation loop of the enzyme, increases enzymatic activity.42 It has been shown previously that the protein kinase A–dependent phosphorylation of c-Src at serine 17 is followed by Y416, and the addition of PP2 does not prevent the serine 17 phosphorylation but does block the Y416 phosphorylation.43 We now show that c-Src activity is increased by fenoldopam and that blocking c-Src with PP2 prevents the AT1R downregulation. We speculate that the D5R is responsible for the activation of c-Src, because AT1R downregulation by fenoldopam is still operational in D1R uncoupled cells. Our future studies will concentrate on the intermediate pathway connecting the D5R to c-Src activation.
In summary, we have demonstrated that, in RPTCs from human kidneys, there is a transregulatory pathway whereby the D5R receptor downregulates the AT1R. This represents a novel mechanism to explain the dynamic balance between the natriuretic dopaminergic and antinatriuretic angiotensin systems in the kidney.
Perspectives
The human kidney is the primary organ responsible for orchestrating a balance between sodium reabsorption and excretion to maintain fluid and electrolyte balance and, ultimately, blood pressure. Two principal pathways have been identified that act to increase sodium reabsorption (the renin-angiotensin system mainly stimulated by angiotensin II via AT1R) or decrease sodium reabsorption (the dopaminergic system working through dopamine produced in the kidney). It has been of interest to determine which cell-surface receptors are responsible for transducing these counterbalancing signals to enable the development of targeted pharmaceuticals. In this article we have delineated how these 2 systems work to regulate each other. More importantly, we have identified a novel AT1R regulatory pathway that relies on the independent action of the D5R that is mechanistically distinct from the D1R.
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Acknowledgments |
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Sources of Funding
These studies were supported in part by grants from the National Institutes of Health (HL74940, HL23081, DK39308, HL068686, and DK52612).
Disclosures
None.
Received September 5, 2007; first decision September 22, 2007; accepted November 28, 2007.
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