Abstract 155: Group IV Cytosolic Phospholipase A2a Disruption Protects Against Angiotensin II-Induced Hypertension and End Organ Damage

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Abstract

Previously we have shown that Group IV cytosolic phospholipase A2α (cPLA2α) is critical for the development of angiotensin (Ang) II-induced hypertension, cardiovascular dysfunction and fibrosis. This study was conducted to determine the role of cPLA2α in renal dysfunction and end organ damage associated with Ang II-induced hypertension. Eight weeks old male wild type (cPLA2α+/+) and cPLA2α knockout (cPLA2α-/-)mice were infused with Ang II (700 ng/kg/min) or its vehicle for 2 weeks and systolic blood pressure (SBP) was measured weekly by the tail cuff method. Ang II increased SBP (mmHg) in cPLA2α+/+ mice to a greater degree than in cPLA2α-/- mice (125 ± 2 to 186 ± 7 vs. 125 ± 2 to 132 ± 2 respectively, P< 0.05). Ang II caused renal fibrosis as indicated by accumulation of α-smooth muscle actin, transforming growth factor-β-positive cells and collagen deposition in the kidneys of cPLA2α+/+ but not cPLA2α-/- mice. Ang II infusion increased reactive oxygen species production in the kidney measured by 2-hydroxyethidium fluorescence (AU), in cPLA2α+/+ mice (16.14 ± 0.61 vehicle vs. 24.08 ± 0.61 Ang II P < 0.05) but not in cPLA2α-/- mice (16.93 ± 0.58 vehicle vs. 17.19 ± 0.93 Ang II). Mice were placed in metabolic cages to monitor their water intake and urine output. After 13 days of Ang II infusion, 24 hr water intake was increased (4.33 ± 0.14 ml to 8.17 ± 0.27 ml P < 0.05) in cPLA2α+/+ mice but not in cPLA2α-/- mice (4.87 ± 0.22 ml to 4.8 ± 0.27 ml). Twenty-four hr urine output (μl) was increased to a greater extent in cPLA2α+/+ mice (423.33 ± 67.26 to 2030.94 ± 191.58 P < 0.05) vs. cPLA2α-/- mice (374.37 ± 66.89 to 787.37 ± 126.50). Urine osmolality (mOsm/kg) was decreased (3778.33 ± 240.21 to 1620 ± 129.23 P < 0.05) in cPLA2α+/+ but not in cPLA2α-/- mice (4042 ± 306.07 to 3372.5 ± 43.27), and proteinuria (mg/24hr) increased to a greater extent in cPLA2α+/+ mice (2.07 ± 0.11 to 6.99 ± 0.34 P < 0.05) vs. cPLA2α-/- mice (1.95 ± 0.07 to 3.03 ± 0.20 in cPLA2α-/-). These data suggest that cPLA2α contributes to Ang II-induced hypertension, associated renal dysfunction and end organ damage, most likely due to release of arachidonic acid, activation of NADPH oxidase and generation of ROS. Thus, cPLA2α could serve as a potential therapeutic target in the treatment of hypertension and end organ damage.

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