mPGES-1 protects against DOCA-salt hypertension via inhibition of oxidative stress or stimulation of NO/cGMP.
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.
Jia
Zhanjun
Z
Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah 84132, USA.
Aoyagi
Toshinori
T
Yang
Tianxin
T
D000704:Analysis of Variance; D000818:Animals; D001795:Blood Pressure Determination; D006152:Cyclic GMP / Q000378:metabolism*; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology*; D007124:Immunoenzyme Techniques; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D000071876:Prostaglandin-E Synthases; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000502:physiology*
D017382:Reactive Oxygen Species; D003900:Desoxycorticosterone; D012313:RNA; D012964:Sodium; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D006152:Cyclic GMP