Cytosolic Phospholipase A2α Is Essential for Renal Dysfunction and End-Organ Damage Associated With Angiotensin II-Induced Hypertension

BACKGROUND The kidney plays an important role in regulating blood pressure (BP). cPLA2 alpha in the kidney is activated by various agents including angiotensin II (Ang II) and selectively releases arachidonic acid (AA) from tissue lipids, generating pro- and antihypertensive eicosanoids. Since activation of cPLA2 alpha is the rate-limiting step in AA release, this study was conducted to determine its contribution to renal dysfunction and end-organ damage associated with Ang II-induced hypertension. METHODS cPLA2 alpha(+/+) and cPLA2 alpha(-/-) mice were infused with Ang II (700 ng/kg/min) or its vehicle for 13 days. Mice were placed in metabolic cages to monitor their food and water intake, and urine was collected and its volume was measured. Doppler imaging was performed to assess renal hemodynamics. On the 13th day of Ang II infusion, mice were sacrificed and their tissues and blood collected for further analysis. RESULTS Ang II increased renal vascular resistance, water intake, and urine output and Na+ excretion, decreased urine osmolality, and produced proteinuria in cPLA2 alpha(+/+) mice. Ang II also caused accumulation of F4/80(+) macrophages and CD3(+) T cells and renal fibrosis, and increased oxidative stress in the kidneys of cPLA2 alpha(+/+) mice. All these effects of Ang II were minimized in cPLA2 alpha(-/-) mice. CONCLUSION cPLA2 alpha contributes to renal dysfunction, inflammation, and end-organ damage, most likely via the action of pro-hypertensive eicosanoids and increased oxidative stress associated with Ang II-induced hypertension. Thus, cPLA2 alpha could serve as a potential therapeutic target for treating renal dysfunction and end-organ damage in hypertension.