Inhibition of pressure natriuresis in mice lacking the AT2 receptor

Background Angiotensin II type 2 (AT(2)) receptor knockout mice have higher blood pressures than wild-type mice; however, the hypertension is imperfectly defined. We tested the hypothesis that renal mechanisms could be contributory. Methods. We conducted pressure-natriuresis-diuresis experiments, measured renal cortical and medullary blood flow by laser Doppler methods, and explored cytochrome P450-dependent arachidonic acid metabolism by means of reverse transcription-polymerase chain reaction. Results. Blood pressure was 15 mm Hg higher in ATP receptor knockout mice than in controls, and pressure diuresis and natriuresis curves were shifted rightward. At similar renal perfusion pressures (113 to 118 mm Hg), wild-type mice excreted threefold more sodium and water than AT(2) receptor knockout mice. Fractional sodium and water excretion curves were shifted rightward in parallel. Renal blood flow ranged between 6.72 and 7.88 mL/min/g kidney wet weight (kwt) in wild-type and between 5.84 and 6.15 mL/min/g kwt in ATI receptor knockout mice. Renal vascular resistance was increased in AT(2)A receptor knockout mice. Cortical blood flow readings leveled at 2.5 V in wild-type and 1.5 V in AT(2) receptor knockout mice. Medullary blood flow readings ranged between 0.8 and 1.0 V and increased 116% in wild-type mice as renal perfusion pressure was increased. This increase did not occur in AT(1) receptor knockout mice. The glomerular filtration rate (GFR) was similar in both groups at approximately 1 mL/min/g kwt. Renal microsomes from AT(2) receptor knockout mice had less activity in hydroxylating arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-meter) than controls, whereas renal AT(1) receptor gene expression was increased in AT(2) receptor knockout mice. Conclusions. Hemodynamic and tubular factors modify renal sodium handling in AT(2) receptor knockout mice and may cause hypertension. AT(2) receptor disruption induces alterations of other regulatory systems, including altered arachidonic acid metabolism, that may contribute to the intrarenal differences observed between AT(2) receptor knockout and wild-type mice.