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(Hypertension. 1997;29:957-961.)
© 1997 American Heart Association, Inc.

Articles

Renal Immunocytochemical Distribution and Pharmacological Properties of the Dual Angiotensin II/AVP Receptor

Carlos B. Gonzalez; Victoria L. M. Herrera; ; Nelson Ruiz-Opazo

From the Section of Molecular Genetics (N.R.-O., V.L.M.H.) and Cardiology (V.L.M.H.), Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston (Mass) University School of Medicine, and Department of Physiology, Austral University, Valdivia, Chile (C.B.G.).

Correspondence to Nelson Ruiz-Opazo, PhD, Section of Molecular Genetics, Whitaker Cardiovascular Institute, Center for Advanced Biomedical Research, Boston University Medical School, 700 Albany St, W-609, Boston, MA 02118-2394.

	Abstract

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Abstract We have recently characterized a novel angiotensin II/vasopressin (Ang II/AVP) dual receptor coupled to adenylate cyclase and responding with equal sensitivity to Ang II and AVP. To gain insight into putative renal physiological roles of the dual Ang II/AVP receptor, we determined its pharmacological binding properties and renal immunocytochemical distribution. The effective displacement of [³H]AVP by [1-deamino-Val¹⁴,D-Arg⁸]-vasopressin (DVDAVP), a specific antidiuretic AVP analogue, supports a V₂-type AVP receptor characteristic of the Ang II/AVP receptor. Displacement of ¹²⁵I–Ang II by losartan but not by PD 123319 defines the Ang II/AVP receptor as a novel AT₁ receptor isoform coupled to adenylate cyclase, in contrast to prototype Ca²⁺-mobilizing AT₁ receptors. Neither Ang II nor AVP displace each other, corroborating the predicted discrete binding domains for Ang II and AVP but presenting an enigma for the dissection of putative Ang II–and AVP-specific hierarchical roles of the dual Ang II/AVP receptor. The renal cytolocalization of the Ang II/AVP receptor to the outer medullary thick ascending limb tubules and inner medullary collecting ducts is consistent with the well-established AVP stimulation of sodium and water reabsorption in these tubules. These data suggest that the Ang II/AVP receptor might provide the molecular basis for the observed similar stimulatory effects of Ang II and AVP on renal tubular sodium and fluid reabsorption at physiological hormone concentrations.

Key Words: renin-angiotensin system • membrane proteins • sodium • water-electrolyte balance

	Introduction

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Vasopressin (arginine vasopressin, AVP) and angiotensin II (Ang II) hormone polypeptides modulate a variety of physiological functions centrally and peripherally.^{1 2 3} Consistent with these diverse physiological roles, several isoreceptors for both AVP and Ang II have been recently characterized.^{4 5 6 7 8 9 10 11 12 13} Of these, the isolation and characterization of a novel dual Ang II/AVP receptor has provided for the first time molecular evidence of a functional link between the Ang II and AVP hormonal systems.¹⁰ Intriguingly, this Ang II receptor subtype, albeit dual, is coupled to the adenylate cyclase second messenger system, in contrast to prototype Ang II receptors coupled to Ca²⁺-mobilizing second messenger pathways.

The accepted classification of Ang II receptor subtypes, AT₁ and AT₂, is based on the differential binding of nonpeptide Ang II receptor antagonists: AT₁ receptors bind to losartan and AT₂ receptors to PD 123319.¹⁴ Ang II receptors of both subtypes have been cloned, AT_1A,^{9 10 11 12} AT_1B,¹¹ and AT₂.^{5 8} For AVP receptors, at least two classes of isoreceptors have been named: type 1 (V₁) is functionally coupled to Ca²⁺-mobilizing effector pathways; and type 2 (V₂), frequently designated as the antidiuretic type, is coupled to the adenylate cyclase system and found in the kidney.¹⁵ A V_1b subtype that stimulates corticotropin release has been described in the anterior pituitary.¹⁶ Molecular cloning and functional characterization of V_1a,⁷ V_1b,¹³ and V₂^{4 6} receptors have been performed.

After the initial characterization of the novel dual Ang II/AVP receptor,¹⁰ the resolution of its pharmacological profile, hence classification, and cell-specific localization were prioritized as pertinent issues relevant to the dissection of its putative physiological roles. Its dual nature also prompted the determination of the hierarchical interaction of Ang II and AVP on the dual Ang II/AVP receptor. The relative abundance of the Ang II/AVP receptor mRNA in rat kidney as delineated by Northern blot analysis¹⁰ targeted the investigation of the cell-specific expression of the Ang II/AVP receptor in different renal epithelia. Here we report the pharmacological ligand binding characteristics and renal immunohistochemical distribution of the Ang II/AVP receptor polypeptide.

	Methods

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Binding Studies in Cos1 pMAM-A1V9 Transfectants
The 2.25-kb A1V9 cDNA encoding the Ang II/AVP receptor¹⁰ was subcloned directionally (5' to 3') into the Nhe I site of the pMAMNeo expression vector (Clontech). The pMAM-A1V9 expression vector was then transfected into Cos1 cells, and stable neomycin-resistant transfectants (pMAM-A1V9 cells) were selected and maintained in medium containing G418 for subsequent studies. Binding assays were done essentially as described¹⁰ with the following specifications: Competition curves of [³H]AVP (specific activity, 50 Ci/mmol) binding were determined with 1.4x10⁶ cells (P-35 dishes). Incubations were done for 20 minutes at 37°C with 5 nmol/L [³H]AVP in the presence of increasing concentrations of the different competitors tested. Competition studies of ¹²⁵I–Ang II (specific activity, 2000 Ci/mmol) binding were performed with 1.4x10⁶ cells (P-35 dishes). Incubations were done for 20 minutes at 37°C with 0.1 nmol/L ¹²⁵I–Ang II in the presence of increasing concentrations of the different competitors. Specific binding was determined as the difference between the total radioactivity bound to cells and the radioactivity bound to blanks containing 1 µmol/L Ang II or 10 µmol/L AVP.

Immunocytochemistry
We used a polyclonal rabbit antiserum raised against the Ang II/AVP receptor synthetic peptide K₁₉₃DELKDEE₂₀₀ in this study.¹⁰ Immunocytochemistry on coronal sections of rat kidney was performed essentially as described,¹⁷ with the following specifications: The tissue specimens used in this study were fixed in Bouin's solution (Sigma Chemical Co) and subsequently paraffin embedded. After application of the primary antibody (at 1:100 dilution) to the tissue sections, the samples were immunostained by the peroxidase/antiperoxidase method with a peroxidase/antiperoxidase kit (DAKO Corp) and 3,3'-diaminobenzidine as a substrate-chromogen reagent. No immunostaining was observed on kidney sections when the antipeptide antibody was coincubated with the antigenic peptide (100 mg/L) or replaced by preimmune serum at a 1:100 dilution (control shown in Fig 2E). Kidney sections were examined with a microscope (Nikon Optiphot) and photographed at optimal magnification.

View larger version (126K): [in this window] [in a new window]   Figure 2. Immunohistochemical localization of angiotensin II/arginine vasopressin (Ang II/AVP) receptor in rat kidney. Immunocytochemistry was performed on coronal sections of rat kidney (see "Methods"). A, Polyclonal antipeptide antibody raised against extracellular peptide aa193-aa200 of the Ang II/AVP receptor10 showed specific staining of outer medullary tubules (OM) and inner medullary collecting ducts (IM). OS indicates outer stripe; IS, inner stripe; and C, cortex. B, Higher magnification of inner stripe region (area B in panel A) shows strong immunoreactivity in numerous basal infolding of the plasma membrane of thick ascending limb (TAL) cells. C, Higher magnification of the boundary between outer and inner medullary areas (area C in panel A); D, higher magnification of inner medulla (area D of panel A); both show specific cell membrane immunoreactivity of the collecting ducts (CD). E, Control section incubated with preimmune serum (see "Methods") demonstrating minimal background immunostaining.

	Results

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Pharmacological Dissection of Ang II/AVP Receptor Ligand Binding Characteristics
Because of the novelty of a dual-peptide ligand/single-receptor system, we investigated the interaction of Ang II and AVP for the specific binding of the other. As seen in Fig 1A, 10 µmol/L Ang II did not displace AVP as measured in [³H]AVP binding experiments. Conversely, 10 µmol/L AVP did not displace ¹²⁵I–Ang II binding (data not shown). This is consistent with two discrete and independent binding sites for Ang II and AVP, respectively, and is in accordance with the predicted discrete locations of the antipeptide sequence–based binding domains.¹⁰ However, this provides no clues as to putative hierarchical physiological regulation of the dual Ang II/AVP receptor.

View larger version (18K): [in this window] [in a new window]   Figure 1. Pharmacological characteristics of the angiotensin II/arginine vasopressin (Ang II/AVP) receptor expressed in Cos1 pMAM-A1V9 cells. A, Competition for [3H]AVP specific binding by various AVP analogues and Ang II () is presented compared with competition by unlabeled AVP () per se. indicates V2 agonist (DVDAVP)18 ; , V1 antagonist ([d-(CH33)5,Tyr(Me)]-AVP)19 ; and , V1/V2 antagonist ([d-(CH2)5,D-Ile4]-AVP)33 (see "Methods" for definitions of agonist and antagonist abbreviations). B, Competition for 125I–Ang II specific binding by Ang II (), losartan (), and PD 123319 (). Each graph is representative of at least three independent experiments performed in triplicate. Mean percent variation, 6.5%.

The effective displacement of [³H]AVP by [1-deamino-Val¹⁴,D-Arg⁸]-vasopressin (DVDAVP), a highly potent and specific antidiuretic AVP analogue¹⁸ (K_d, low-affinity=109±23 nmol/L) (Fig 1A, Table), supports the V₂-type characteristic of this kidney-derived Ang II/AVP receptor functionally coupled to the adenylate cyclase system. Consistently, a specific V₁-type receptor antagonist, [ß-mercapto-ß,ß-cyclopentamethylenepropionyl¹,O-Me-Tyr²,Arg⁸]-AVP (abbreviated [d-(CH₂)₅,Tyr(Me)]-AVP),¹⁹ exhibited markedly less displacement (K_i low-affinity >13 000 nmol/L) (Fig 1A, Table). Interestingly, the V₁/V₂-specific antagonist was similarly ineffective in displacing [³H]AVP (Fig 1, Table). It should be mentioned that under the experimental conditions used for the [³H]AVP competition binding experiments (presence of 5 nmol/L [³H]AVP, see "Methods"), only the low-affinity binding sites can be readily detected (K_d low-affinity AVP=8.7±1.2 nmol, see Table).

View this table: [in this window] [in a new window]   Table 1. Pharmacological Parameters of Angiotensin II/Arginine Vasopressin Receptor Expressed in Cos1 pMAM-A1V9 Cells

Recent studies with the newly developed nonpeptide Ang II antagonists have revealed the existence of two Ang II receptor subtypes, AT₁ and AT₂.¹⁴ All the known physiological and biochemical functions mediated by Ang II are blocked by the AT₁-specific antagonist. Binding studies with losartan (an AT₁-specific antagonist) and PD 123319 (an AT₂-specific antagonist)²⁰ (Fig 1B) define the Ang II/AVP receptor as a novel AT₁ receptor isoform coupled to adenylate cyclase. It is noted that Ang II and losartan showed almost identical displacement isotherms reflected in a K_i high of 0.05±0.017 nmol/L and K_i low of 14±3.08 nmol/L for losartan and Ang II, respectively (Fig 1B, Table). PD 123319 did not displace ¹²⁵I–Ang II binding up to concentrations of 10^-5 mol/L (Fig 1B).

Renal Distribution of the Ang II/AVP Receptor
AVP is known to regulate nephron function by stimulating the intracellular production of cAMP in several tubular segments along the nephron.²¹ AVP does not stimulate adenylate cyclase in the early portion of the nephron (the proximal convoluted tubule, proximal straight tubule, and thin descending limb of the loop of Henle).²¹ In contrast, AVP strongly activates adenylate cyclase in all segments of the nephron located beyond the hairpin turn of the loop of Henle, including the thin ascending limb, medullary and cortical portions of the thick ascending limb, and early distal convoluted tubules and collecting ducts.²¹ The observed physiological effects of AVP along the different segments of the nephron are mediated by G_s-coupled V₂ receptors. The existence of a single or multiple V₂ isoreceptors accounting for the different renal physiological effects remains to be determined.

To assess the putative involvement of the Ang II/AVP receptor in some or all of the known AVP renal physiological targets,²¹ we performed immunohistochemical studies in rat kidney preparations using the polyclonal antipeptide antibody raised against aa₁₉₃-aa₂₀₀ of the second extracellular loop of the Ang II/AVP receptor¹⁰ (see "Methods"). As shown in Fig 2, the immunostaining revealed strong immunoreactivity in tubules of the outer and inner medulla, consistent with the presence of Ang II/AVP receptors in the thick ascending limb of the loop of Henle and collecting ducts (Fig 2). These segments of the nephron are known prominent physiological targets of AVP action.²¹ The specificity of immunocytolocalization was ascertained by the negative staining observed when the antipeptide antibody was coincubated with the antigenic peptide, the nonreactivity of the preimmune serum (Fig 2E and 2F), and the variant intensities of immunoreactivity in different renal epithelia and the consistent immunoreactivity within specific renal tubular types.

	Discussion

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The renal immunocytochemical distribution and pharmacological characterization of the Ang II/AVP receptor suggest that this receptor is a prominent renal target for Ang II and AVP. The direct renal effect of physiological concentrations (10^-12 to 10^-10 mol/L) of Ang II are primarily antidiuretic and antinatriuretic.^{22 23 24 25 26 27 28} This Ang II concentration is well within the range of the Ang II/AVP receptor sensitivity (Ang II EC₅₀=10^-10 mol/L),¹⁰ and its renal cytolocalization (tubular segments of the outer and inner medulla) is also consistent with the Ang II direct stimulatory effect on tubular sodium and fluid reabsorption.²⁷ Likewise, the half-maximal responses (cAMP accumulation) to AVP for the different renal tubular segments range between 0.2x10^-10 and 5x10^-9 mol/L,²¹ which is well within the range of the Ang II/AVP receptor half-maximal response (cAMP accumulation) to AVP (10^-10 mol/L).¹⁰ The renal Ang II/AVP receptor cytolocalization to the outer medullary tubules (collecting ducts and thick ascending limb of Henle) and inner medullary collecting ducts is remarkably consistent with the well-established AVP stimulation via V₂ receptors of sodium and water reabsorption in the thick ascending limb and collecting tubules.²¹ Thus, the existence of the Ang II/AVP receptor might provide the molecular basis for the observed similar antinatriuretic and antidiuretic effects of Ang II and AVP on renal tubular sodium and fluid reabsorption at physiological hormone concentrations.^{21 27}

In situ hybridization studies of the rat V₂ receptor have been reported,²⁹ delineating the presence of this receptor mainly in inner medullary collecting ducts of the medullopapillary region. However, judging by the long exposure time (2 months) in this previous experiment,²⁹ its abundance is relatively low. Immunocytochemical studies on this V₂ receptor have not been reported for evaluation of its membrane and cell-specific localization.

Additionally, the Ang II/AVP receptor exhibits classification characteristics consistent with AT₁ and V₂ isoreceptor subtypes, specifying the dual receptor as an AT₁/V₂-type receptor. Coupling to the adenylate cyclase system distinguishes the Ang II_AT1/AVP_V2 receptor from renal Ca²⁺-mobilizing AT₁ receptors. Renal Ang II receptors coupled to the adenylate cyclase second messenger system have been previously described,² although inhibition of cAMP was observed. Resolution of this difference remains to be elucidated.

The characterization of the Ang II/AVP receptor demonstrates a functional link between Ang II and AVP hormonal systems. However, an understanding of the interplay between Ang II and AVP through the dual Ang II/AVP receptor remains an important issue because current data show that Ang II and AVP do not displace each other, concordant with molecularly proven distinct binding domains.¹⁰ A mechanism for putative hierarchical physiological interaction remains to be elucidated. Strategic targeted disruption and/or mutagenesis of the Ang II/AVP receptor gene will be necessary for assessment of its integrated physiological role in the kidney and other organ systems where it is detected, such as the liver, lung, adrenal gland, aorta, cardiac atria, and brain.¹⁰ The importance of this investigation is highlighted by the fact that AT_1A and AT₂ receptor knockout mouse models do not exhibit altered renal pathophysiological phenotypes,^{30 31 32} consistent with the redundancy of multiple Ang II receptor isoforms, or intuitively, with the likelihood that the Ang II/AVP receptor might be a critical renal AT₁ receptor.

	Acknowledgments

 
Nelson Ruiz-Opazo is an Established Investigator of the American Heart Association. This work was partially supported by National Institutes of Health grant HL-48903. We thank Dr Joan Keiser (Parke-Davis) for providing us with PD 123319. Losartan potassium was kindly provided by Dr Ronald D. Smith (DuPont Merck Pharmaceutical Co).

Received June 14, 1996; first decision July 12, 1996; accepted October 10, 1996.

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