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Abstract: FR-OR074

Central EP3 Receptors Mediate Salt-Sensitive Hypertension and Immune Activation

Session Information

Category: Hypertension and CVD

  • 1403 Hypertension and CVD: Mechanisms

Authors

  • Xiao, Liang, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Breyer, Richard M., Vanderbilt University, Nashville, Tennessee, United States
  • Harrison, David G., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Prostaglandin E2 (PGE2) has been implicated in the generation of reactive oxygen species and inflammation associated with hypertension. Proteins oxidatively modified by reactive isolevoglandins (isoLGs) accumulate in dendritic cells (DCs) leading to subsequent activation of T lymphocytes. The local signals that stimulate DCs to accumulate isoLG adducted proteins remain undefined. We hypothesized that PGE2 via its EP3 receptor contributes to DC activation in hypertension.

Methods

EP3-/- mice and wild type (WT) littermates were exposed to sequential hypertensive stimuli involving an initial exposure to the nitric oxide synthase inhibitor L-NAME (LN) in drinking water, a 2 week washout period, and a subsequent 4% high salt diet (HS). Lentiviral vectors encoding shRNA targeting EP3 receptor were administered intracerebroventricularly to knockdown EP3 receptor expression in the central nervous system.

Results

In WT mice, this protocol increased systolic pressure from a baseline of 123±2 to 148±8 mmHg (p<0.05), and renal CD4+ and CD8+ effector memory T cells by 2 to 3 fold. This was associated with marked increases in superoxide production in the kidney and a striking accumulation of isoLG protein adducts in splenic DCs. The increases in blood pressure, renal T cell infiltration, renal superoxide production and DC isoLG formation were completely prevented in EP3-/- mice. Interestingly, we found that EP3 receptor, among all EP receptors, is highly expressed in the organum vasculosum laminae terminalis (OVLT) in the brain, LNHS treatment induced an upregulation of COX-2 expression and downregulation of EP3 receptor in the OVLT. To test the hypothesis that central EP3 receptor contributes to the LNHS induced hypertension and renal inflammation, WT mice received intracerebroventricular injection of lentiviral vectors encoding shRNA targeting EP3 receptor and then subjected to the same LNHS treatment. These mice were also protected from salt induced hypertension and renal inflammation like the EP3-/- mice.

Conclusion

These findings provide new insight involving EP3 receptor in the central nervous system and sympathetic activation in salt induced hypertension and provide additional information as to how PGE2 modulates inflammation in this conditions.

Funding

  • Other NIH Support