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(Hypertension. 1997;30:725.)
© 1997 American Heart Association, Inc.

Articles

Localization of the Dopamine D₁ Receptor Protein in the Human Heart and Kidney

Ryoji Ozono; Damian P. O’Connell; Zhi-Qin Wang; Allan F. Moore; Hironobu Sanada; Robin A. Felder; Robert M. Carey

From the Departments of Medicine and Pathology, University of Virginia Health Sciences Center (Charlottesville); and the Department of Pharmacology and Therapeutics, University College Cork, Ireland (D.P.O’C.).

Correspondence to Robert M. Carey, MD, Box 395, University of Virginia Health Sciences Center, Charlottesville, Va 22908. E-mail RMC4C{at}virginia.edu

	Abstract

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Abstract The dopamine D₁ receptor has recently been identified in the rat heart and kidney. In the present study, using Western blot analysis and light microscopic immunohistochemistry, we examined D₁ receptor protein expression in the human kidney and heart. Antipeptide polyclonal rabbit antiserum was raised against the third extracellular domain of the native receptor and affinity-purified using a protein-A column. Selectivity of the antiserum was validated by recognition of the D₁ receptor expressed in stably transfected LTK^- cells and Sf-9 cells. The immunohistochemical staining for D₁ receptor protein was distributed throughout the atrium and ventricular myocardium and in the coronary vessels. In the kidney, positive immunoreactive signal was detected in the proximal and distal tubules, the collecting ducts, and the large intrarenal vasculature, whereas staining was absent in the juxtaglomerular (JG) cells and the glomeruli. D₁ receptor antiserum preadsorbed against the immunizing peptide did not produce significant staining. In Western blot analysis, a single 55-kD band was detected for the D₁ receptor in membranes from the D₁ receptor transfected Sf-9 cells but not in nontransfected cells. In the heart and kidney, we detected a 55-kD band as well as an additional 40-kD band, which may reflect partial degradation of the receptor protein. These results provide the first evidence for the localization of the dopamine D₁ receptor protein in the human heart and kidney. The similar distribution of this subtype receptor in the human heart and kidney to that in the rat supports the possible (patho)physiological significance of the peripheral dopamine system in humans.

Key Words: immunohistochemistry • dopamine receptors • heart • kidney • human

	Introduction

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Dopamine, an established neurotransmitter in the central nervous system, is also an important peripheral physiological regulator in its own right. It exerts physiological functions through specific dopamine receptors distributed in the various tissues. Recent advances in molecular biology have afforded the identification of at least five subtypes of dopamine receptors.^{1 2 3 4 5} These newly described receptors have been shown to correspond pharmacologically and biochemically to the classic D₁-like (D_1A and D_1B in the rat, or D₁ and D₅ in humans) and D₂-like (D_2L, D_2S, D₃, and D₄) receptor subtypes on the basis of their ability to stimulate or inhibit adenyl cyclase, respectively.⁶ It is well established that the kidney possesses ligand binding capacity for the D₁-like receptor agonists (ie, fenoldopam) and antagonists (ie, SCH 23390), and stimulation of the renal D₁-like receptor is associated with significant diuresis and natriuresis.^{7 8}

We have recently provided evidence for the expression of the D_1A receptor gene and protein in the rat kidney,^{9 10 11} heart,¹² and adrenal gland¹³ using molecular biology–based techniques. Also, we have demonstrated that administration of the selective D₁-like receptor agonist fenoldopam produces a remarkable increase in sodium excretion and renal plasma flow in humans.^{14 15} A previous light microscopic autoradiographic study, using H³-SCH 23390 as ligand, has shown the D₁-like receptor binding sites in the proximal and distal tubules and intrarenal arteries of the human kidney.¹⁶ Such localization awaits molecular biological confirmation since dopaminergic agents or ligands may cross-react with other monoamine receptors, including adrenergic or serotonin receptors. More importantly, none of the available D₁-like receptor ligands differentiates the D₁ from D₅ receptor subtype. It is not clear to which subtype of the D₁-like receptor family (D₁, D₅, or both) the D₁-like receptor binding sites in the human kidney, as previously identified by autoradiography,¹⁶ belong. At present, there is no direct evidence available that the D₁ receptor is expressed in human peripheral tissues, although our preliminary results showed the presence of the D₁ receptor mRNA in the human kidney.¹⁷ The present study, using light microscopic immunohistochemistry and Western blot analysis, demonstrates that the newly cloned D₁ receptor protein is expressed in the human kidney and heart, to our knowledge for the first time.

	Methods

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Light Microscopic Immunohistochemistry
Antipeptide polyclonal rabbit antibody was raised against a synthetic peptide sequence derived from the predicted human D₁ receptor. The specific sequence of the peptide was GSGETQPFC, amino acids 299 to 307, located on the third extracellular domain.² The antibody was IgG-affinity purified by the method of Lindmark et al.¹⁸ A full-length human D₁ receptor cDNA was subcloned in the expression vector pCMV₅ (a kind gift from Dr Marc Caron, Duke University Medical Center, Durham, NC) at the Xba I site and transfected into the murine fibroblast LTK^- cells as previously described.^{19 20} These transfected LTK^- cells have been shown to exhibit specific ligand binding and functional activity characteristic of a D₁ dopamine receptor coupled to stimulation of adenylyl cyclase.²⁰ Selectivity of the antibody was validated by its ability to recognize the human D₁ receptor expressed in stably transfected LTK^- cells and Sf-9 cells by immunocytochemistry and Western blot analysis, respectively.

Immunocytochemistry was performed as previously described.^{9 10 11 12 13} Cells grown on plastic chamber slides (Lab-Tek, Chamber Slides, Nunc) were fixed in 1% paraformaldehyde in phosphate-buffered saline (PBS) at room temperature. The cells were treated with the antiserum diluted at 1:500 overnight at 4°C, and the staining was visualized using an avidin-biotin immunoperoxidase reaction (Vectastatin ABC Kit, Vector Labs). The cells were lightly counterstained with hematoxylin.

Human kidney tissues (n=4) were obtained as discarded surgical specimens during nephrectomy due to renal carcinoma and trauma not involving the whole organ. The portions of kidney tissues not showing macroscopic abnormality were subjected to study. The discarded cardiac tissues (n=3) were from patients undergoing coronary artery bypass grafting. The ages of the patients ranged from 45 to 75 years. The study protocol was approved by the Human Investigation Committee of the University of Virginia School of Medicine. Immediately after dissection, tissues were cut into blocks about 1 mm³ in size and then immersion-fixed in 1% paraformaldehyde in PBS for 1 to 2 hours. The tissues were cryoprotected overnight at 4°C in 30% sucrose in PBS, and frozen sections (8 to 12 µm) were cut. Endogenous peroxidase was blocked using 0.3% H₂O₂ in methanol for 30 minutes, and then the nonspecific secondary antibody binding site was blocked for 30 minutes with 3% normal goat serum and 1% nonfat dry milk in PBS. Thereafter, the sections were incubated for 36 to 48 hours at 4°C with one of the following, diluted in 1.5% normal goat serum and 0.5% nonfat dry milk in PBS: (1) anti-D₁ receptor primary antiserum or (2) anti-D₁ receptor primary antiserum preadsorbed against its pure peptide immunogen. For the preadsorption, antiserum was incubated overnight at 4°C with a 10-fold molar excess of the peptide. After washes in PBS, the immunostaining was detected with an avidin-biotin immunoperoxidase reaction (Vectastain ABC kit, Vector Lab) followed by visualization with diaminobenzidine (Sigma Fast DAB Tablets, Sigma). Tissue sections were lightly counterstained with hematoxylin, dehydrated, and placed under coverslips.

Western Blot Analysis of D₁ Receptor Protein
Western blot analysis was performed as previously described^{11 12} with slight modifications. The freshly obtained renal and cardiac tissues were minced and homogenized with Tissuemizer (Tekmar Corp) in Buffer A (10% glycerol, 20 mmol/L Tris-HCl, pH 7.3, 100 mmol/L NaCl, 2 mmol/L phenylmethyl sulfonyl fluoride, 2 mmol/L EDTA, 2 mmol/L EGTA, 10 mmol/L sodium orthovanadate, 10 µg/L leupeptin, 10 µg/L aprotinin, and 10 µg/L trypsin inhibitor). The homogenate was centrifuged at 30 000g for 30 minutes at 4°C. The pellet was resuspended in Buffer B (Buffer A with 1% NP-40 [Sigma]), stirred for 1 hour at 4°C, and centrifuged again at 30 000g for 30 minutes at 4°C. The supernatant was used for the analysis. For positive controls, plasma membranes from Sf-9 cells expressing human D₁ receptor were obtained commercially (RBI). Membranes of the human tissues and the transfected and nontransfected Sf-9 cells were subjected to SDS-polyacrylamide gel electrophoresis (5% acrylamide stacking gel and 8% running gel) as described.^{11 12} The resolved proteins were transferred by electroblotting (15 V for 20 minutes, Trans Blot SD DNA, Bio-Rad) onto a nitrocellulose sheet (BA-S 83, Schleicher & Schuell). The nitrocellulose sheet was blocked in Tween 20 solution (0.1% Tween 20, 10 mmol/L Tris-HCl, pH 7.5, 150 mmol/L NaCl, and 5% nonfat dry milk) for 2 hours at room temperature, incubated with the anti-D₁ receptor antiserum (1:1000 dilution in Tween 20 solution) for 2 hours, and reacted with a peroxidase-labeled anti-rabbit IgG donkey serum (1:5000 dilution) for 1 hour, and the specific bands were visualized using chemiluminescence (ECL Western Blotting Detecting Kit, Amersham).

	Results

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Immunoperoxidase Histochemistry
The D₁ receptor transfected LTK^- cells were positively stained with the antiserum, whereas incubation of the antiserum did not give any staining in nontransfected LTK^- cells (Fig 1).

View larger version (142K): [in this window] [in a new window]   Figure 1. Light photomicrographs of dopamine D1 receptor transfected LTK- cells demonstrating the positive staining for the D1 receptor (1:500 dilution). Left, D1 receptor transfected LTK- cells; right, nontransfected LTK- cells. Magnification x400.

In the heart, homogeneous staining for the D₁ receptor was obtained throughout the myocardium of the atrium and ventricle (Fig 2A and 2C). The coronary vessels were also stained. Consecutive sections processed with the antibody preadsorbed against its peptide immunogen produced no staining (Fig 2B and 2D).

View larger version (154K): [in this window] [in a new window]   Figure 2. Light photomicrographs of human heart demonstrating positive immunostaining for the dopamine D1 receptor (1:250 dilution). Left column, Representative sections of human atrium (A) and ventricle (C) treated with antiserum against the D1 receptor; right column, consecutive sections of the atrium (B) and ventricle (D) treated with antiserum preadsorbed against the peptide antigen. Magnification x400.

In the kidney, immunohistochemical staining for the D₁ receptor was obtained in both the renal cortex and medulla. Immunoreactive staining was localized in the proximal and distal tubules, the collecting ducts, and the medial layer of large intrarenal arteries (Fig 3A, 3C to 3F). In contrast, no significant staining was observed in the glomeruli, JG cells, and small intrarenal vascular branches (Fig 3A, 3C, 3E). Consecutive sections processed with the antiserum preadsorbed against the immunizing peptide did not produce significant staining (Fig 3B, 3G).

View larger version (131K): [in this window] [in a new window]   Figure 3. Light photomicrographs of human kidney demonstrating positive immunostaining for the dopamine D1 receptor (1:500 dilution). A, Section of renal cortex treated with the D1 receptor antiserum demonstrating positive staining in proximal tubules but not in the glomerulus (x200). B, Consecutive section of renal cortex treated with the preadsorbed antiserum (preabsorption control for A, x200). C, High-power view of renal cortex treated with the D1 receptor antiserum showing positive signal in proximal tubules and absence of staining in the glomerulus and the juxtaglomerular cells (x400). D, Section of renal cortex treated with D1 receptor antiserum demonstrating proximal tubule staining and intense staining in the medial layer of a large intrarenal artery (x125). E, Section of renal cortex treated with the D1 receptor antiserum demonstrating no staining in several small intrarenal arteries and positive staining in proximal tubules (x400). F, Section of renal medulla treated with D1 receptor antiserum showing positive staining in the collecting ducts (x200). G, Consecutive section of renal medulla treated with the preadsorbed antiserum (preabsorption control for F) (x200).

Western Blot Analysis
A single 55-kD band for dopamine D₁ receptor was detected in the transfected (lane 3) but not in the nontransfected Sf-9 cells (lane 6). In the atrium (lane 1), ventricle (lane 2), and renal cortex (lane 4) and medulla (lane 5), the same 55-kD band was observed, while an additional 40-kD band also was present (Fig 4).

View larger version (59K): [in this window] [in a new window]   Figure 4. Western blot analysis of the dopamine D1 receptor protein in Sf-9 cells (5 µg protein per lane), human heart, and kidney (40 µg protein per lane). A single band (55 kD) for the D1 receptor was detected in the transfected Sf-9 cells (lane 3), atrium (lane 1), ventricle (lane 2), and in the renal cortex (lane 4) and medulla (lane 5), whereas this band was absent in nontransfected Sf-9 cells (lane 6). An additional 40-kD band also was observed in the heart and kidney.

	Discussion

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An increasing body of evidence suggests that dopamine, as a local paracrine substance, plays a major role in the physiological functions of peripheral organs including the kidney^{6 7 8 14 15} and heart¹² in animals. In the present study, we provide the first molecular evidence for peripheral localization of the D₁ receptor in humans. The antiserum, directed toward the third extracellular region of the putative D₁ receptor protein, allows for the identification of the D₁ receptor subtype that is otherwise not distinguishable by current pharmacological or ligand binding techniques. The D₁ receptor gene encodes a protein of 446 amino acids having a deduced relative molecular mass of 49 296 and shares 62% homology with D₅ receptor at the protein level. The specific portion of the D₁ receptor sequence was chosen as the target for the antiserum production because the sequence has no homology to any other gene products, including other dopamine receptor subtypes. We found in previous rat studies^{10 11 12} that antiserum against this domain gave excellent results in terms of specificity and intensity of the immunoreactive signal. The amino acid sequence of the third extracellular domain is conserved in humans and the rat with the exception of only one amino acid. The selectivity of the antibody was validated by its ability to recognize native human D₁ receptor expressed in stably transfected LTK^- cells. In addition, the signal disappeared after preadsorption of the antibody with the pure immunizing peptide. Consistent with the calculated molecular weight of the D₁ receptor, a single band was detected at 55 kD from Sf-9 cells transfected with the human D₁ receptor by Western blot analysis. In the human tissues, we obtained the same 55-kD band and an additional 40-kD band, which may represent degraded receptor protein. Therefore, the antiserum is able to recognize specifically the human D₁ receptor.

We recently demonstrated in the rat that both D_1A receptor gene⁹ and protein^{7 10 11} are expressed in the proximal and distal tubules, collecting ducts, and renal vessels including JG cells, but not in the glomeruli.¹⁰ In the kidney, dopamine is locally produced²¹ and regulates renal hemodynamics and tubular sodium reabsorption as a local autocrine/paracrine substance.^{8 21} Present localization of the human D₁ receptor in the proximal and distal tubules, collecting ducts, and the medial layer of intrarenal arteries, as well as its absence in the glomeruli, is in good agreement with the results obtained by a previous autoradiographic study.¹⁶ In our previous physiological studies, D₁-like receptor stimulation with the selective D₁-like receptor agonist fenoldopam leads to an increase in fractional sodium excretion and renal plasma flow without affecting glomerular filtration rate in humans.^{14 15} The present immunohistochemical study provides anatomic evidence indicating that these effects are most likely mediated via stimulation of D₁ receptors within specific portions of human nephrons. However, further studies are required to elucidate whether the D₅ receptor is also expressed in the human kidney.

D_1A receptor mRNA and protein have been identified in rat JG cells.^{10 11} D₁-like receptor agonists stimulate renin release via stimulation of the D_1A receptor in rat JG cells.^{11 22} D₁-like receptor binding sites in human JG cells were also detected using an autoradiographic technique with H³-SCH 23390 as ligand.¹⁶ In contrast, no immunoreactive signal for D₁ receptor in the JG cells was detected in humans in the present study. The reason for this difference is not clear. However, our previous study in humans showed that selective D₁-like receptor stimulation had no significant effect on plasma renin activity.¹⁵ It is likely therefore that the D₁ receptor is not significantly involved in the control of renin release in humans.

The gene and protein of D_1A receptor are expressed in the rat myocardium and coronary arteries.¹² Fenoldopam, a specific D₁-like receptor agonist, stimulated adenyl cyclase in the plasma membrane fraction of the rat ventricle.¹² Dopamine is detectable in the rat heart homogenate,^{23 24} indicating that it may be locally produced. Although the function of the D₁ receptor in the heart is only poorly understood, evidence is beginning to accumulate that the peripheral dopaminergic system may regulate cardiac function. Recent studies suggest that the D₁ receptor is involved in the development of left ventricular hypertrophy^{25 26} and congestive heart failure.²⁷ Chromosomal mapping studies in spontaneously hypertensive rats²⁶ indicated that left ventricular weight, not blood pressure, was most tightly correlated with a marker for the D_1A receptor locus. In the present study, we confirmed that the D₁ receptor is also distributed in the human myocardium and coronary vessels. The possible role of the D₁ receptor in the heart remains to be determined.

In summary, we have demonstrated the D₁ receptor protein expression and localization in the kidney and heart in humans. The expression of the D₁ receptor in human kidney and heart constitutes evidence for the presence of a peripheral dopamine system in humans. The similarity of distribution of the receptor in the human heart and kidney to that in the rat supports the possible physiological and/or pathophysiological significance of the peripheral dopamine system in humans.

	Acknowledgments

 
This work was supported in part by grant R01-HL-49575 (Dr Carey) from the National Institutes of Health. The authors wish to thank Suzanne J. Botkin for her technical assistance.

Received March 15, 1997; first decision May 14, 1997; accepted May 27, 1997.

	References

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