Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor

The angiotensin subtype-1 (AT₁) receptor mediates renal prostaglandin E₂ (PGE₂) production, and pharmacological blockade of the angiotensin subtype-2 (AT₂) receptor potentiates the action of angiotensin II (Ang II) to increase PGE₂ levels. We investigated the role of the AT₂ receptor in prostaglandin metabolism in mice with targeted deletion of the AT₂ receptor gene. Mice lacking the AT₂ receptor (AT₂-null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT₂-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF_1α (a stable hydrolysis product of prostacyclin [PGI₂]) and PGE₂ levels than did WT mice, and had similar increases in PGE₂ and 6-keto-PGF_1α in response to dietary sodium restriction and Ang II infusion. In contrast, AT₂-null mice had lower PGF_2α levels compared with WT mice during basal conditions and in response to dietary sodium restriction or infusion of Ang II. RIF cAMP was markedly higher in AT₂-null mice than in WT mice, both during basal conditions and during sodium restriction or Ang II infusion. AT₁ receptor blockade with losartan decreased PGE₂, PGI₂, and cAMP to levels observed in WT mice. To determine whether increased vasodilator prostanoids prevented hypertension in AT₂-null mice, we treated AT₂-null and WT mice with indomethacin for 14 days. PGI₂, PGE₂, and cAMP were markedly decreased in both WT and AT₂-null mice. Blood pressure increased to hypertensive levels in AT₂-null mice but was unchanged in WT. These results demonstrate that in the absence of the AT₂ receptor, increased vasodilator prostanoids protect against the development of hypertension.

The renin-angiotensin system constitutes a major hormonal cascade regulating fluid and electrolyte balance and blood pressure (BP), the principal effector of which is angiotensin II (Ang II) (1). The vast majority of the physiological effects of Ang II are mediated by the subtype-1 (AT₁) angiotensin receptor; the function of the subtype-2 (AT₂) receptor remains to be determined (2). AT₂ receptors are present in the kidney and are upregulated by sodium depletion and Ang II (3, 4).

Ang II stimulates production of prostacyclin (PGI₂) and prostaglandin E₂ (PGE₂) (5). The angiotensin receptor subtype mediating renal prostanoid formation is largely unknown. We have shown previously in the rat kidney that the AT₁ receptor mediates Ang II–induced PGE₂ production and that pharmacological blockade of the AT₂ receptor potentiates Ang II–induced PGE₂ levels (6). We also demonstrated that Ang II stimulates an increase in renal PGF_2α through an action at the AT₂ receptor (7).

This study was conducted to evaluate the role of the AT₂ receptor in prostaglandin metabolism and to investigate the mechanisms involving prostaglandins in maintaining normal BP. To address these issues, we used a novel microdialysis technique and mice with targeted disruption of the AT₂ receptor gene to monitor changes in 6-keto-PGF_1α (a stable hydrolysis product of PGI₂), PGE₂, PGF_2α, and cAMP (the major second messenger of PGE₂ and PGI₂) in renal interstitial fluid (RIF) (5, 8).

BP, V, and U_NaV responses to dietary sodium restriction and Ang II infusion. BP was slightly but significantly higher in AT₂-null mice (n = 10) than in WT mice (n = 10) at baseline (Table 1). Sodium restriction did not alter BP in either AT₂-null or WT mice. Ang II infusion increased BP significantly in AT₂-null mice but not in WT mice. V and U_NaV were similar in AT₂-null and WT mice. In response to sodium restriction, V was unchanged but U_NaV was significantly reduced in both WT and AT₂-null mice. Ang II infusion decreased V and U_NaV significantly in AT₂-null mice but not in WT mice.

Table 1

BP and urinary volume and sodium excretion in AT₂-null and WT mice

RIF PGE₂, PGF_2α, 6-keto-PGF_1α, and cAMP responses to dietary sodium restriction. Figure 1a depicts PGE₂ levels during normal sodium intake and after 7 days of dietary sodium restriction. During normal sodium intake, PGE₂ was significantly increased in AT₂-null mice compared with WT mice. Dietary sodium restriction increased PGE₂ both in AT₂-null and WT mice. In sodium-restricted animals, PGE₂ levels in AT₂-null mice were more than 2-fold higher than in WT mice. Figure 1b demonstrates PGF_2α levels. PGF_2α was significantly lower in AT₂-null mice than in WT mice during normal sodium intake. Dietary sodium restriction increased PGF_2α in WT mice but significantly decreased PGF_2α in AT₂-null mice. In sodium-restricted animals, PGF_2α levels were more than 10-fold higher in WT mice than in AT₂-null mice. Figure 1c shows RIF levels of 6-keto-PGF_1α. Basal levels of 6-keto-PGF_1α were higher in AT₂-null mice than in WT mice. In both WT and AT₂-null mice, 6-keto-PGF_1α increased significantly in response to sodium restriction. There was no significant difference in the incremental change to sodium restriction between WT and AT₂-null mice. AT₂-null mice had approximately 26-fold higher cAMP levels (Figure 1d) than did WT mice during normal sodium intake. Low sodium intake resulted in no significant change in cAMP in either AT₂-null or WT mice.

Figure 1

RIF PGE₂ (a), PGF_2α (b), 6-keto-PGF_1α (c), and cAMP (d) in mice (n = 10) lacking the AT₂ angiotensin receptor (filled bars) and in WT mice (n = 10; open bars), on normal or low dietary sodium (Na) intake. (a) *P < 0.0005 vs. WT; ⁺P < 0.005, ⁺⁺P < 0.001 vs. normal sodium intake. (b) *P < 0.001 vs. WT; ⁺P < 0.05, ⁺⁺P < 0.001 vs. normal sodium intake. (c) *P < 0.001 vs. WT; ⁺P < 0.01, ⁺⁺P < 0.001 vs. normal sodium intake. (d) *P < 0.0005 vs. WT.

RIF PGE₂, PGF_2α, 6-keto-PGF_1α, and cAMP responses to chronic Ang II infusion. AT₂-null mice had higher PGE₂ levels (Figure 2a) than did WT mice during vehicle infusion. Ang II infusion increased PGE₂ in both WT and AT₂-null mice, the increase being significantly greater in WT mice. After Ang II infusion, AT₂-null mice had PGE₂ levels similar to those in WT mice. AT₂-null mice had lower PGF_2α levels (Figure 2b) than did WT mice during vehicle infusion. In WT mice, PGF_2α was increased approximately 4-fold by chronic Ang II infusion, whereas in AT₂-null mice, there was no significant change in PGF_2α levels in response to Ang II. Responses of 6-keto-PGF_1α to exogenous Ang II are shown in Figure 2c. Basal control levels of 6-keto-PGF_1α were higher in AT₂-null mice than in WT mice. Both WT and AT₂-null mice had significant increases in 6-keto-PGF_1α in response to Ang II, and there was no difference in these responses between the two. cAMP values (Figure 2d) were significantly higher in AT₂-null mice than in WT mice, both basally and in response to Ang II. Ang II did not significantly alter cAMP in either WT or AT₂-null mice.

Figure 2

RIF PGE₂ (a), PGF_2α (b), 6-keto-PGF_1α (c), and cAMP (d) in mice (n = 10) lacking the AT₂ angiotensin receptor (filled bars) and in WT mice (n = 10; open bars) during the vehicle control period (Control) and after 7 days of continuous infusion of Ang II. (a) *P < 0.01 vs. WT; ⁺P < 0.05, ⁺⁺P < 0.0005 vs. control. (b) *P < 0.001, **P < 0.0001 vs. WT; ⁺P < 0.0001 vs. control. (c) *P < 0.0005 vs. WT; ⁺P < 0.05 vs. control. (d) *P < 0.01, **P < 0.001 vs. WT; ⁺P < 0.002 vs. control.

BP responses to indomethacin. In AT₂-null mice, BP increased progressively and dramatically well into the hypertensive range in response to intraperitoneally administered indomethacin (5 mg/kg/d) (Figure 3). There was no change in BP on any day of the vehicle time control. BP before vehicle administration was 102 ± 5 mmHg and was 103 ± 2 mmHg after 14 days of vehicle administration. There was no change in BP in WT mice in response to indomethacin (Figure 3).

Figure 3

SBP of mice (n = 10) lacking the AT₂ angiotensin receptor (triangles) and of WT mice (n = 10, circles) during vehicle infusion (day 0) and during continuous intraperitoneal infusion of indomethacin (5 mg/kg/d) for 14 days. *P < 0.001 vs. day 0 and WT. ⁺P < 0.0001 vs. day 0 and WT.

RIF PGE₂, PGF_2α, and cAMP responses to chronic indomethacin administration. PGE₂ (Figure 4a) values were about 3.5-fold higher in AT₂-null mice than in WT mice on day 0 before indomethacin administration. In response to 14 consecutive days of indomethacin administration, PGE₂ was significantly decreased in both WT and AT₂-null mice. PGE₂ values were not significantly different in WT and AT₂-null mice after 14 days of indomethacin administration. PGF_2α levels (Figure 4b) were more than 3-fold lower in AT₂-null mice than in WT mice at baseline. Indomethacin lowered PGF_2α both in WT and AT₂-null mice. In indomethacin-treated animals, PGF_2α was significantly lower in AT₂-null mice than in WT mice. Indomethacin decreased 6-keto-PGF_1α levels significantly in both WT and AT₂-null mice, such that levels were not significantly different between the two (Figure 4c). cAMP levels (Figure 4d) in WT mice were low and were unchanged by indomethacin. In AT₂-null mice, cAMP levels were relatively high at baseline and were markedly reduced.

Figure 4

RIF PGE₂ (a), PGF_2α (b), 6-keto-PGF_1α (c), and cAMP (d) in mice (n = 10) lacking the AT₂ angiotensin receptor (filled bars) and in WT mice (n = 10; open bars) during the vehicle control period (Control) and after 14 days of indomethacin administration (5 mg/kg/d intraperitoneally). (a) *P < 0.0005 vs. WT; ⁺P < 0.005, ⁺⁺P < 0.0005 vs. control. (b) *P < 0.001, **P < 0.0001 vs. WT; ⁺P < 0.0001 vs. control.(c) *P < 0.001 vs. WT; ⁺P < 0.0001, **P < 0.0001 vs. control. (d) *P < 0.001 vs. WT. ⁺⁺P < 0.0005 vs. control.

RIF PGE₂, 6-keto-PGF_1α, and cAMP responses to AT₁ receptor blockade in AT₂-null mice. As shown in Figure 5, control values for PGE₂, 6-keto-PGF_1α, and cAMP in AT₂-null mice were 39 ± 7, 39 ± 4, and 16 ± 3 pg/min, respectively. In response to losartan, PGE₂ decreased (P < 0.0001) to less than one third of control values and to a value similar to that of WT mice. Similarly, 6-keto-PGF_1α decreased to about 40% of control values (P < 0.0001). Losartan caused a parallel reduction of cAMP (P < 0.0001) to values similar to those of WT mice.

Figure 5

RIF PGE₂ (a), 6-keto-PGF_1α (b), and cAMP (c) in WT mice (n = 5) before and 2 hours after intravenous losartan administration (10 mg/kg). ⁺P < 0.0001 vs. control.

RIF PGE₂ and PGF_2α responses to AT₂ receptor blockade in sodium-restricted WT mice. Figure 6 depicts the incremental increase in PGE₂ and PGF_2α in response to dietary sodium restriction for 5 days in the presence or absence of continuous intravenous infusion of PD. Sodium restriction increased both PGE₂ and PGF_2α in mice receiving only vehicle infusion. AT₂ receptor blockade with PD further increased PGE₂ but decreased the PGF_2α response to sodium restriction (both P < 0.01).

Figure 6

Incremental increase in RIF PGE₂ (a) and PGF_2α (b) in WT mice (n = 5) in response to 5 days of dietary sodium restriction in the presence or absence of the AT₂ receptor antagonist PD123319 (PD; 50 μg/kg/min). *P < 0.001 vs. vehicle control.

This study demonstrates that Ang II acts at the AT₁ receptor to stimulate both PGI₂ and PGE₂ production in the kidney. PGE₂ is the major renal prostanoid and has substantially greater vasodilator potency than PGI₂ in the rat kidney (5). PGI₂ is the major metabolite of arachidonic acid in vascular endothelial cells (6). The baseline increase in renal PGE₂ and 6-keto-PGF_1α in AT₂-null mice is the result of interruption of receptor cross-talk and the presence of “unopposed” AT₁ receptors in these mice, as AT₁ receptor blockade normalized PGE₂ and 6-keto-PGF_1α in AT₂-null mice. These observations suggest that the AT₂ receptor has a tonic inhibitory action on the production of PGI₂ and PGE₂, which is driven by the AT₁ receptor.

It is generally appreciated that Ang II can stimulate PGI₂ and PGE₂ production in nonrenal tissues. Studies using isolated vascular smooth muscle cells and isolated perfused heart preparations have demonstrated that Ang II stimulates PGI₂ release through an interaction at AT₁ receptors (11–15). However, the angiotensin subtype receptor responsible for renal PGE₂ and PGI₂ formation has not been studied systematically. The results of the present study show that both renal PGI₂ and PGE₂ production are stimulated in parallel by either endogenous (sodium restriction) or exogenous Ang II.

PGI₂ and PGE₂ are both formed from the precursor PGH₂, which is a product of cyclooxygenase action on its substrate, arachidonic acid. PGF_2α, another major renal prostanoid, can also be formed directly from PGH₂ or, alternatively, by conversion from PGE₂ through the action of PGE₂ 9-ketoreductase (5). Prostaglandins are paracrine or autocrine substances, acting locally in the tissues in which they are formed (5). Because of their rapid degradation on passage across the lungs, these substances are not detectable in appreciable quantities in the circulation. However, prostanoids can be assayed and changes monitored in RIF with a high degree of sensitivity (6). PGE₂ and PGF_2α are produced in renal interstitial and collecting duct cells and in the endothelium of vasa recta, and they participate in the regulation of renal function (16, 17). The production of these autacoids is augmented by pressor hormones, including Ang II via stimulation of phospholipase A2, to form arachidonic acid substrate from membrane phospholipids (5, 18). Ang II stimulates the endothelial release of arachidonic acid metabolites (19–21). We have shown previously in the rat that Ang II stimulates renal PGE₂ production through the AT₁ receptor (6). Our present results are consistent with earlier observations in the normal rat kidney that conversion of PGE₂ to PGF_2α by 9-ketoreductase is enhanced by sodium depletion (22, 23).

An important finding of the present study is that Ang II acts at the AT₂ receptor to stimulate PGF_2α, probably by conversion from PGE₂. At baseline, mice lacking the AT₂ receptor had increased RIF levels of PGE₂ and low levels of PGF_2α. In WT mice, both sodium restriction (endogenous Ang II) and chronic infusion of a small quantity of exogenous Ang II increased 6-keto-PGF_1α, PGE₂, and PGF_2α. Similarly, in AT₂-null mice, sodium restriction and chronic Ang II infusion increased 6-keto-PGF_1α and PGE₂. In marked contrast to WT mice, however, in AT₂-null mice, both exogenous and endogenous Ang II failed to increase PGF_2α. These results were confirmed by experiments showing that sodium restriction increased PGE₂, PGI₂, and PGF_2α, and by separate experiments showing that AT₂ receptor blockade with PD blocked the increase in PGE₂ in WT mice. Our results underscore the physiological importance of the AT₂ receptor in the formation of PGF_2α, most likely through conversion from PGE₂ by 9-ketoreductase. Our data, however, do not permit determination of the effects, if any, of the AT₂ receptor on PGH₂ metabolism. Our data demonstrate that the increase in basal PGE₂ in AT₂-null mice is largely related to absence of tonic inhibition of the AT₂ receptor on AT₁ receptor–mediated PGE₂ production.

The interaction between the renin-angiotensin system and renal eicosanoids is fundamental to the regulation of body fluid and sodium homeostasis (8). PGI₂ and PGE₂ stimulate, whereas PGF_2α inhibits, renin secretion (24). AT₂ receptor–mediated stimulation of PGF_2α formation, and its inhibitory effect on renin secretion, is in agreement with recent findings that the AT₂ receptor may indirectly mediate vasodilation (9). PGE₂ inhibits sodium reabsorption in the cortical and medullary collecting ducts and leads to natriuresis (25). Sodium depletion increases renal Ang II formation (26), and it is likely that the resulting increase in conversion of PGE₂ to PGF_2α is related to increased Ang II formation and stimulation of the AT₂ receptor. The decrease in sodium excretion during sodium restriction is likely mediated by AT₁ receptors in renal tubule cells in both WT and AT₂-null mice.

The tonic inhibitory action of the AT₂ receptor on AT₁ receptor–mediated PGI₂ and PGE₂ production may be due to several possible factors. (a) Nitric oxide, which is increased by AT₂ receptors, has been described to inhibit cyclooxygenase under some conditions (27, 28). (b) cGMP, also increased by AT₂ receptors, may affect prostaglandin metabolism (28). (c) Bradykinin, also increased by AT₂ receptors, can stimulate the production of nitric oxide and eicosanoids in the intact kidney (29). (d) The AT₂ receptor may stimulate epoxide production through the cytochrome P450 system, which may compete with arachidonic acid for metabolism by cyclooxygenase, resulting in inhibition of PGI₂ and PGE₂ formation (30, 31). These possibilities will need to be resolved in future studies.

PGF_2α, the product of PGE₂ metabolism by 9-ketoreductase, binds mainly to the recently cloned FP receptor, resulting in a rise in intracellular calcium (32). The FP receptor is thought to mediate vasoconstriction. PGF_2α also can bind to EP₁ and EP₃ receptors, both of which also mediate vasoconstriction (32). In AT₂-null mice, the decrease in PGF_2α may contribute to the absence of hypertension by reducing peripheral and/or renal vasoconstriction.

PGE₂ has been shown to stimulate adenylyl cyclase via the EP₂ and EP₄ receptors with the generation of cAMP, which acts as its second messenger (8, 32). These 2 receptors mediate vascular smooth muscle relaxation. cAMP is extruded from target cells by a prostanoid-sensitive membrane transporter and can be measured in the RIF. Our data demonstrate that cAMP levels were high in AT₂-null mice (PGE₂ and PGI₂ levels also were elevated) compared with WT mice. An unanticipated finding was the failure of cAMP to increase in WT mice in response to sodium restriction or Ang II in proportion to the increase in PGE₂. The parallel reduction of PGE₂, 6-keto-PGF_1α, and cAMP by indomethacin suggests, however, that PGE₂ and/or PGI₂ are very likely responsible for elevated cAMP in AT₂-null mice. Failure of cAMP to increase substantially in response to sodium restriction or Ang II in AT₂-null mice may indicate maximum stimulation of cAMP production in the basal state.

Both PGE₂ and PGI₂ are vasodilators, and excessive vasodilator prostanoid accumulation in the absence of the AT₂ receptor may account for the absence of hypertension in this model. To test this hypothesis, we administered the cyclooxygenase inhibitor indomethacin and monitored BP. In response to indomethacin, which decreased renal 6-keto-PGF_1α, PGE₂, and PGF_2α to low levels, BP steadily rose into the hypertensive range. These results suggest that increased PGI₂ and PGE₂ in AT₂-null mice prevented the increase in BP that otherwise would have occurred, most likely owing to a reduction of other vasodilators such as bradykinin and/or nitric oxide, which are stimulated via the AT₂ receptor (6). It is also possible that in addition to decreasing vasodilator prostanoid production, indomethacin may have selectively inhibited vasodilator prostanoid signal transduction in target cells, as has been demonstrated in the cerebral microcirculation (33). Therefore, the action of indomethacin to increase BP could be related to inhibition of both vasodilator prostanoid synthesis and action.

There are several limitations to the present study. (a) We were unable to measure plasma renin activity or Ang II concentrations because volume depletion might have altered RIF autacoid levels. (b) Although we were able to monitor PGE₂ and PGF_2α levels, we were not able to measure the activity of PGE₂ 9-ketoreductase directly. (c) Indomethacin has been reported to inhibit enzyme systems and cell signaling processes other than cyclooxygenase activity, including cAMP- and cGMP-phosphodiesterases, cAMP-dependent protein kinases and endogenous phosphorylation, active Ca²⁺ transport, and adenosine uptake (33). However, none of these potential actions of indomethacin could account for the ability of indomethacin to raise systemic BP or to decrease prostanoid or cAMP levels.

In summary, we have demonstrated that absence of the AT₂ receptor results in increased PGI₂ and PGE₂ and decreased PGF_2α levels in the kidney, both basally and in response to Ang II. These findings establish a physiological role of the AT₂ receptor in renal prostanoid production and metabolism. We also demonstrated that the renal vasodilator prostanoids PGE₂ and PGI₂ are stimulated via the AT₁ receptor, providing counterregulatory vasodilation in opposition to the vasoconstrictor action of Ang II. Most importantly, we demonstrated that in the absence of the AT₂ receptor, increased levels of these vasodilator prostanoids prevent the development of hypertension.

This work was supported by grants HL-47669 and HL-57503 (to H.M. Siragy), HL-35323 and HL-58205 (to T. Inagami), and HL-49575 and HL-59948 (to R.M. Carey) from the National Institutes of Health (NIH). H.M. Siragy is the recipient of Research Career Development Award K04-HL-03006 from the NIH.

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