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(Hypertension. 1996;28:916-918.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin II Type 2 Receptor Inhibits Cell Proliferation and Activates Tyrosine Phosphatase

Satoshi Tsuzuki; Teruyoshi Matoba; Satoru Eguchi; Tadashi Inagami

the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Tadashi Inagami, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146.

	Abstract

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The angiotensin II type 2 (AT₂) receptor inhibits basic fibroblast growth factor–induced proliferation of R3T3 fibroblast cells and transiently stimulates a vanadate-sensitive phosphotyrosine phosphatase, strongly suggesting that AT₂ is a mitogen inhibitor. We generated AT₂ gene–null mice that showed increased blood pressure, indicating the hypotensive action of AT₂. However, inhibition of renomedullary AT₂ by selective antagonists, as reported by Sassard and associates, show that AT₂ suppresses pressure natriuresis. Thus, both AT₁ and AT₂ work in the direction of sodium retention, suggesting a unique role for angiotensin II in the kidney in terms of blood pressure regulation and sodium metabolism.

Key Words: angiotensin II • type 2 receptor • cell proliferation • phosphotyrosine phosphatase • receptor gene deletion

	Introduction

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Of the two isoforms of Ang II receptor (AT₁ and AT₂), AT₁ is considered to account for most of the conventional functions of Ang II and its pathophysiological effects, such as cardiovascular hypertrophy,^{1 2 3} whereas the mechanisms of action of AT₂ and its pathophysiological significance are largely unclear. AT₂ receptor expression is abundant during fetal development, but this abundance is followed by a rapid decline in most organs immediately after birth.⁴ Interestingly, the AT₂ receptor can be reexpressed in pathological situations that involve tissue remodeling or repair, such as vascular neointima formation⁵ and wound healing.⁶

A study performed in vivo has shown that administration of the AT₂ agonist CGP42112A to rats prevented neointima formation after arterial injury.⁶ In in vitro studies, it has been shown that in cultured coronary endothelial cells isolated from the neonatal vasculature, the AT₂ receptor mediates inhibition of the mitogenic effect of bFGF in endothelial cells, which is an important regulator of angiogenesis.⁷ Moreover, in endothelial or vascular smooth muscle cells transfected with AT₂,⁸ it caused growth inhibition in opposition to the effects of AT₁. Thus, all of these physiological studies provide a negative link between the AT₂ receptor and cell growth.

Efforts to investigate the antimitogenic role and intracellular signaling mechanisms of the AT₂ isoform have been hampered by the lack of an appropriate and reliable cell system in which the AT₂ receptor is expressed and cell growth can be manipulated without drastic effects on receptor function. In the present study, we used R3T3 mouse fibroblast cells that selectively express the AT₂ subtype⁹ and examined the AT₂-mediated antimitogenic action and its intracellular signaling. Here we report the AT₂-mediated inhibition of cell proliferation and activation of PTP in R3T3 cells.

	Methods

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Materials
R3T3 cells were a gift from Dr David Dudley of Warner-Lambert Parke-Davis Co. CGP42112A [N--nicotinoyl-N--(N--benzyloxycarbonyl-Arg) Lys-His-Pro-Ile] was purchased from Neo-system; bovine bFGF was from Upstate Biotechnology; DMEM and fetal calf serum were from GIBCO BRL; and p-Npp, PMSF, Na-orthovanadate, and other chemicals were from Sigma Chemical Co.

Proliferation Assay
R3T3 cells were seeded at a density of 2.0x10⁵ in 12-well plates in 2 mL DMEM with 10% fetal calf serum and incubated for 48 hours. The cells were then washed with serum-free DMEM and kept in serum-free DMEM for an additional 72 hours to obtain a quiescent state. bFGF and test substances (Ang II and CGP42112A) were added in 2 mL fresh, serum-free medium; the cells were incubated for 72 hours, rinsed twice with PBS, and harvested with trypsin-EDTA (0.05% trypsin and 0.02% EDTA) solution. Cell number was determined directly by using a Coulter counter. In all experiments with losartan, a specific AT₁ receptor blocker, or PD123319, a specific AT₂ blocker, the compounds were added 10 minutes before Ang II treatment.

PTP Assay
The effect of Ang II on PTP activity was measured with the synthetic substrate p-Npp by a spectrophotometric method that determines the production of p-nitrophenol¹⁰ and by using the ³²P-labeled peptide substrate Raytide (Oncogene Science) as previously described.¹⁶ Confluent and 72-hour serum-depleted R3T3 cells seeded in six-well plates were incubated for various times at 37°C with 10^-7 mol/L Ang II or for 10 minutes. The cells were washed twice with ice-cold PBS, mechanically scraped, and collected by centrifugation at 3000g for 5 minutes at 4°C. Cells were resuspended in 0.1 mL hypotonic buffer (50 mmol/L Tris HCl, pH 7.0, containing 0.1 mmol/L EDTA, 0.1 mmol/L EGTA, 0.1% [vol/vol] ß-mercaptoethanol, 20 µg/mL aprotinin, 20 µg/mL leupeptin, and 0.1 mmol/L PMSF) and quickly lysed in a Dounce homogenizer. Pellets were collected by centrifugation at 1000g for 5 minutes and resuspended in the hypotonic buffer containing 0.1% Triton X-100 and 10% glycerol. The postnuclear fraction was collected as the supernatant after centrifugation at 15 000g for 5 minutes and then used for the PTP assay.¹¹ Equal amounts of protein from each sample were preincubated for 5 minutes at 30°C in a 160-µL aliquot of buffer containing 40 µL of 5x reaction buffer (200 mmol/L Tris HCl, pH 7.0, 50 mmol/L dithiothreitol, 25 mmol/L EDTA, 0.5 µmol/L microcystine-Leu-Arg, and 50 µmol/L ZnCl₂). For experiments with sodium orthovanadate, cells were preincubated for 30 minutes with 1 mmol/L sodium orthovanadate. The reaction was initiated by adding 40 µL p-Npp or [³²P]Raytide as a substrate (50 mmol/L). After a 10-minute incubation, the reaction was stopped by adding 1.8 mL of 0.2 mol/L NaOH, and sample absorbance was measured at 410 nm. The rate of hydrolysis was estimated by using an extinction coefficient for p-Npp of 1.78x10⁴ (mol/L^-1)·cm^-1,¹² or by measuring released ³²P.

	Results

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To examine the effect of Ang II on proliferation of R3T3 cells, cell number was determined directly in a Coulter counter. Compared with quiescent cells, cell number increased by 35%, 133%, and 160% after addition of 0.25, 2.5, and 25 ng/mL bFGF, respectively. Ang II did not alter cell number in quiescent R3T3 cells (data not shown). However, Ang II did inhibit the increase in cell number induced by bFGF. The antiproliferative effect of 10^-7 mol/L Ang II was abolished by 10^-8 mol/L PD123319, a specific AT₂ receptor antagonist, and was mimicked by 10^-6 mol/L CGP42112A, a specific AT₂ agonist at this concentration. These data concerning peptides are in agreement with AT₂'s partial agonistic properties that have been recently reported in other systems.^{13 14}

To explore the signaling mechanisms that lead to antiproliferation via the AT₂ receptor, we measured the effect of Ang II on PTP activity by using the synthetic substrate p-Npp and a spectrophotometric method.⁹ In the presence of the selective inhibitor of Ser/Thr phosphatase, microcystine-Leu-Arg, this assay was shown to be specific for PTP activity.¹⁰ The alkaline phosphatase inhibitor NaF at 50 mmol/L did not affect the reaction. R3T3 cells were preincubated with Ang II, and then PTP activity in the postnuclear cell fraction was determined. Ang II stimulation of PTP was rapid and transient, reaching a maximum in 5 to 10 minutes and returning to basal levels in 30 minutes (Figure). Maximal stimulation occurred at 10^-6 mol/L Ang II, and half-maximal stimulation (0.5±0.03 nmol/L) was comparable with that of antimitogenic activity. The increase in PTP activity was completely suppressed by preincubating the stimulated cells with 1 mmol/L sodium orthovanadate for 30 minutes. PTP activation by Ang II was not influenced by losartan (10^-7 mol/L) and was mimicked by CGP42112A at higher concentrations (10^-7 to 10^-6 mol/L; data not shown), indicating that PTP activation was mediated through the AT₂ receptor.

View larger version (18K): [in this window] [in a new window]   Figure 1. Effect of Ang II on PTP activity in R3T3 cells: time course of Ang II stimulation of PTP activity. Seventy-two-hour serum-depleted cells were treated with Ang II (10-7 mol/L) for the indicated times, and postnuclear fractions were prepared as described in "Methods." PTP activity of the fraction per unit protein was determined and presented as percent of control (unstimulated) PTP activity. Results represent the mean of four separate experiments±SE. *P<.05.

	Discussion

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Studies of R3T3 cells clearly show the AT₂ receptor–mediated action of Ang II on cell proliferation and PTP activity. These cells express the second isoform of the Ang II receptor exclusively but have no detectable or functional AT₁ binding site. Although antimitogenic actions mediated by the AT₂ subtype have been reported,^{6 7 8} the mechanisms underlying these effects have remained unclear.

In the present study, AT₂-mediated inhibition of cell proliferation was seen in bFGF-treated cells but not in serum-depleted cells, indicating that the effect essentially counteracts growth promotion. Recently, Dudley and Summerfelt⁹ reported that actively growing R3T3 cells express AT₂ receptors at a very low level, whereas in confluent and quiescent cells, AT₂ expression was markedly increased. These investigators also showed that addition of serum or growth factors such as bFGF to quiescent cells caused a rapid decrease in the number of AT₂ receptors. These data suggest a possible role for AT₂ in counteracting the mitogenic action of growth factors in R3T3 cells.

The PTP-stimulating effect of Ang II was determined in the postnuclear fraction after preincubation with Ang II. Under our experimental conditions, rapid and transient PTP stimulation by Ang II was observed in confluent and quiescent R3T3 cells. The results obtained with p-Npp were confirmed by using synthetic Raytide labeled with ³²P at the Tyr residue. The fact that Ang II–mediated activation was not observed in sodium vanadate–treated cells indicates that PTP was activated. Brechler et al¹⁵ reported AT₂-mediated PTP activation measured in membrane particulate preparations from PC12W cells with p-Npp as the substrate. In their study, the membrane particulate fraction was incubated directly with Ang II, followed by determination of PTP activity. On the other hand, we reported AT₂-mediated PTP inhibition in sonicated membrane fractions under similar experimental conditions with PC12W cells, except that synthetic Raytide was used as the substrate.^{16 17} These discrepancies may be related to the substrates or membrane preparations used for each PTP assay. However, until the PTP(s) that couples the AT₂ signaling pathway is identified, we cannot exclude the possibility that there may exist more than one PTP, one being negatively and the other positively regulated by the AT₂ receptor.

The correlation between hormonal PTP activation and antiproliferation has recently been reported in somatostatin^{10 11} and dopamine¹⁸ receptors, both of which have a seven domain transmembrane topology and are structurally related to the AT₂ receptor.^{16 19 20} Is AT₂-mediated inhibition of cell proliferation associated with its stimulation of PTP? We also observed that sodium orthovanadate, a PTP inhibitor, significantly stimulated proliferation of R3T3 cells (S.T. et al, unpublished data). These data strongly suggest a possible link between PTP activation and inhibition of cell proliferation through the AT₂ receptor.

AT₁ mediates the mitogenic action of Ang II, presumably by activating mitogen-activated protein kinase, which involves the Tyr phosphorylation signal.^{21 22} Thus, AT₁ and AT₂ work in opposition in the regulation of Tyr phosphorylation and mitogenesis.

Using AT₂ gene–deleted mice, we have shown that AT₂ counteracts AT₁-mediated hypertensive action.²³ Thus, although the mechanisms of AT₁- and AT₂-mediated actions may not be the exact reverse of each signaling step, the overall effect of AT₂ is to counteract the hypertrophic and vasoconstrictor effects of AT₁. Here again, AT₂ seems to counteract AT₁ in blood pressure regulation.

In the kidney, the AT₂-specific antagonist PD123319 was reported to facilitate pressure natriuresis, suggesting that Ang II–stimulated AT₂ works to retain NaCl.^{24 25} The renal tubular action of AT₁ is also to retain NaCl. Thus, it is intriguing to consider the unique relation of the kidney to Ang II, in that both AT₁ and AT₂ respond to this peptide in the direction of salt retention rather than counteracting each other. This may be one of the important roles of the kidney in the genesis and maintenance of hypertension.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II AT1/AT2 = angiotensin II receptor type 1/2 bFGF = basic fibroblast growth factor DMEM = Dulbecco's modified Eagle's medium p-Npp = p-nitrophenyl phosphate PTP = phosphotyrosine phosphatase

	Acknowledgments

 
This work was supported by research grants HL35323 and HL14192 from the National Institutes of Health, Bethesda, Md. We thank Dr David T. Dudley for providing R3T3 cells, Trinita Fitzgerald for technical assistance, and Tina Stack for preparing the manuscript.

Received June 8, 1996; first decision July 11, 1996; accepted July 11, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benefield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonist. Pharmacol Rev. 1993;45:205-251.[Medline] [Order article via Infotrieve]

2. Chiu AT, Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wexler RR, Wong PC, Johnson AL, Timmermans PBMWM. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989;165:196-203.[Medline] [Order article via Infotrieve]

3. deGasparo M, Whitebread S, Mele M, Montani AS, Whitecombe PJ, Ram-joue HP, Kamber B. Biochemical characterization of two angiotensin II receptor subtypes in the rat. J Cardiovasc Pharmacol. 1990;16(suppl 4):S31-S35.

4. Grady EF, Sechi LA, Groffom CA, Schambelan M, Kalinyak JE. Expression of AT₂ receptors in the developing rat fetus. J Clin Invest. 1991;88:921-933.

5. Janiak P, Pillon A, Prost JF, Vilaine JP. Role of angiotensin subtype 2 receptor neointima formation after vascular injury. Hypertension. 1992;20:737-745.[Abstract/Free Full Text]

6. Viswanathan M, Saavedra JM. Expression of angiotensin II AT₂ receptors in the rat skin during experimental wound healing. Peptides. 1992;13:783-786.[Medline] [Order article via Infotrieve]

7. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT₂-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest. 1995;95:651-657.

8. Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, Horiuchi M, Pratt RE, Dzau VJ. The angiotensin II type 2 (AT₂) receptor antagonizes the growth effects of the AT₁ receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci U S A. 1995;10663-10667.

9. Dudley DT, Summerfelt RM. Regulated expression of angiotensin II (AT₂) binding sites in R3T3 cells. Regul Pept. 1993;44:199-206.[Medline] [Order article via Infotrieve]

10. Pan MG, Florio T, Stork PJS. G-protein activation of a hormone-stimulated phosphatase in human tumor cells. Science. 1992;256:1215-1217.[Abstract/Free Full Text]

11. Maher PA. Stimulation of endothelial cell proliferation by vanadate is specific for microvascular endothelial cells. J Cell Physiol. 1992;151:549-554.[Medline] [Order article via Infotrieve]

12. Buscail L, Delesque N, Esteve JP, Saint-Laurent N, Prats H, Clerc P, Robberecht P, Bell GI, Giebow C, Schally AV, Vaysse N, Susini C. Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. Proc Natl Acad Sci U S A. 1994;91:2315-2319.[Abstract/Free Full Text]

13. Dunphy WG, Kumagai A. The cdc25 protein contains an intrinsic phosphatase activity. Cell. 1991;67:189-196.[Medline] [Order article via Infotrieve]

14. Brechler V, Jones PW, Levens NR, deGasparo M, Bottari SP. Agonistic and antagonistic properties of angiotensin analogs at the AT₂ receptor in PC12W cells. Regul Pept. 1993;44:207-213.[Medline] [Order article via Infotrieve]

15. Brechler V, Reichlin S, deGasparo M, Bottari SP. Angiotensin II stimulates protein tyrosine phosphatase activity through a G-protein independent mechanism. Receptors Channels. 1994;2:89-97.[Medline] [Order article via Infotrieve]

16. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993;268:24543-24546.[Abstract/Free Full Text]

17. Takahashi K, Bardhan S, Kambayashi Y, Shirai H, Inagami T. Protein tyrosine phosphatase inhibition by angiotensin II in rat pheochromocytoma cells through type 2 receptor AT₂. Biochem Biophys Res Commun. 1994;198:60-66.[Medline] [Order article via Infotrieve]

18. Florio T, Pan M-G, Newman B, Hershberger RE, Civelli O, Stork PJS. Dopaminergic inhibition of DNA synthesis in pituitary tumor cells is associated with phosphotyrosine phosphatase activity. J Biol Chem. 1992;267:24169-24172.[Abstract/Free Full Text]

19. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveal unique classes of seven transmembrane receptors. J Biol Chem. 1995;268:24589-24542.

20. Tsuzuki S, Ichiki T, Nakakubo H, Kitami Y, Guo D-F, Shirai H, Inagami T. Molecular cloning and expression of the gene encoding human angiotensin II type 2 receptor. Biochem Biophys Res Commun. 1994;200:1449-1454.[Medline] [Order article via Infotrieve]

21. Tsuda T, Kawahara Y, Shii K, Koide M, Ishida Y, Yokoyama M. Vasoconstrictor-induced protein tyrosine phosphorylation in cultured vascular smooth muscle cells. FEBS Lett. 1991;285:44-48.[Medline] [Order article via Infotrieve]

22. Duff JL, Berk BC, Corson MA. Angiotensin II stimulates the pp44 and pp42 mitogen-activated protein kinases in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1992;188:257-264.[Medline] [Order article via Infotrieve]

23. Ichiki T, Labotsky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BLM, Inagami T. Effects on blood pressure and reduced exploratory behavior in mice lacking angiotensin II type 2 receptor. Nature. 1995;377:748-750.[Medline] [Order article via Infotrieve]

24. Lo M, Liu K-L, Lanteime P, Sassard J. Subtype 2 of angiotensin II receptors controls pressure-natriuresis in rats. J Clin Invest. 1995;95:1394-1397.

25. Siragy HM, Carey RM. The subtype-2 (AT₂) angiotensin receptor regulates renal cyclic guanoside 3', 5'-monophosphate and AT₁ receptor-mediated prostaglandin E₂ production in conscious rats. J Clin Invest. 1996;97:1978-1982.[Medline] [Order article via Infotrieve]

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