Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84132, USA.
Hypertension. 2010 Feb;55(2):539-46. doi: 10.1161/HYPERTENSIONAHA.109.144840. Epub 2010 Jan 11.
Microsomal prostaglandin E synthase-1 (mPGES-1) is a recently characterized cytokine-inducible enzyme critically involved in pain and inflammatory response. However, its role in blood pressure regulation is still debatable. The present study was undertaken to examine the effect of mPGES-1 deletion on DOCA-salt hypertension. After 2 weeks of DOCA plus 1% NaCl as drinking fluid, hypertension and sodium retention were more severe in mPGES-1 knockout (KO) mice than in wild-type (WT) controls. The indices of oxidative stress including urinary 8-isprostane and renal thiobarbituric acid-reactive substances were only modestly increased or unchanged in the WT mice but more significantly increased in the KO mice after DOCA-salt. Conversely, in response to DOCA-salt, the indices of antioxidant systems including renal expression of superoxide dismutase-3 and urinary nitrate/nitrite excretion were all significantly elevated in the WT mice but remarkably suppressed in the KO mice. Tempol treatment (50 mg/kg per day) in DOCA-salt KO mice produced a marked attenuation of hypertension, sodium retention, and kidney injury. Immunoblotting demonstrated increased renal expression of mPGES-1 in DOCA-salt WT mice. DOCA-salt induced a nearly 5-fold increase in urinary PGE(2) excretion in the WT mice, and this increase was completely abolished in the KO mice. Together, these results suggest that mPGES-1-derived PGE(2) confers protection against DOCA-salt hypertension likely via inhibition of oxidative stress or stimulation of superoxide dismutase-3 and urinary nitrate/nitrite system.
微粒体前列腺素 E 合酶-1（mPGES-1）是一种最近被描述的细胞因子诱导型酶，在疼痛和炎症反应中起着关键作用。然而，其在血压调节中的作用仍存在争议。本研究旨在研究 mPGES-1 缺失对 DOCA-盐高血压的影响。在给予 DOCA 和 1%NaCl 作为饮用水 2 周后，mPGES-1 基因敲除（KO）小鼠的高血压和钠潴留比野生型（WT）对照组更为严重。WT 小鼠的氧化应激指标，包括尿 8-异前列腺素和肾硫代巴比妥酸反应物质，仅略有增加或不变，但 KO 小鼠在 DOCA-盐后明显增加。相反，在 DOCA-盐作用下，WT 小鼠的抗氧化系统指标，包括肾超氧化物歧化酶-3 的表达和尿硝酸盐/亚硝酸盐排泄，均显著升高，但 KO 小鼠则明显抑制。在 DOCA-盐 KO 小鼠中给予 Tempol 治疗（每天 50mg/kg）可显著减轻高血压、钠潴留和肾脏损伤。免疫印迹显示 DOCA-盐 WT 小鼠肾 mPGES-1 表达增加。DOCA-盐诱导 WT 小鼠尿 PGE（2）排泄增加近 5 倍，而 KO 小鼠则完全消除。综上所述，这些结果表明 mPGES-1 衍生的 PGE（2）可能通过抑制氧化应激或刺激超氧化物歧化酶-3 和尿硝酸盐/亚硝酸盐系统，对 DOCA-盐高血压起到保护作用。
