Central EP3 (E Prostanoid 3) Receptors Mediate Salt-Sensitive Hypertension and Immune Activation

Hypertension. 2019 Dec;74(6):1507-1515. doi: 10.1161/HYPERTENSIONAHA.119.13850. Epub 2019 Nov 4.


We recently identified a pathway underlying immune activation in hypertension. Proteins oxidatively modified by reactive isoLG (isolevuglandin) accumulate in dendritic cells (DCs). PGE2 (Prostaglandin E2) has been implicated in the inflammation associated with hypertension. We hypothesized that PGE2 via its EP (E prostanoid) 3 receptor contributes to DC activation in hypertension. EP3-/- mice and wild-type littermates were exposed to sequential hypertensive stimuli involving an initial 2-week exposure to the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride in drinking water, followed by a 2-week washout period, and a subsequent 4% high-salt diet for 3 weeks. In wild-type mice, this protocol increased systolic pressure from 123±2 to 148±8 mm Hg (P<0.05). This was associated with marked renal inflammation and a striking accumulation of isoLG adducts in splenic DCs. However, the increases in blood pressure, renal T-cell infiltration, and DC isoLG formation were completely prevented in EP3-/- mice. Similar protective effects were also observed in wild-type mice that received intracerebroventricular injection of a lentiviral vector encoding shRNA targeting the EP3 receptor. Further, in vitro experiments indicated that PGE2 also acts directly on DCs via its EP1 receptors to stimulate intracellular isoLG formation. Together, these findings provide new insight into how EP receptors in both the central nervous system and peripherally on DCs promote inflammation in salt-induced hypertension.

Keywords: autonomic nervous system; blood pressure; dendritic cells; inflammation; reactive oxygen species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / physiology
  • Analysis of Variance
  • Animals
  • Biomarkers / metabolism
  • Biopsy, Needle
  • Brain / metabolism
  • Brain / pathology*
  • Dinoprostone / metabolism*
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Hypertension / immunology
  • Hypertension / metabolism*
  • Hypertension / physiopathology*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Random Allocation
  • Real-Time Polymerase Chain Reaction / methods
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism*
  • Sodium, Dietary / administration & dosage*


  • Biomarkers
  • Receptors, Prostaglandin E, EP3 Subtype
  • Sodium, Dietary
  • Dinoprostone
  • NG-Nitroarginine Methyl Ester