MPGES-1 protects against DOCA-salt hypertension via inhibition of oxidative stress or stimulation of NO/cGMP

Abstract

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 PGE2 excretion in the WT mice, and this increase was completely abolished in the KO mice. Together, these results suggest that mPGES-1-derived PGE2 confers protection against DOCA-salt hypertension likely via inhibition of oxidative stress or stimulation of superoxide dismutase-3 and urinary nitrate/nitrite system. © 2010 American Heart Association. All rights reserved.