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T he 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.