Abstract P1113: P2x7 Receptor Plays a Role in Angiotensin II-Induced Hypertension and Vascular Remodeling

Abstract

Introduction: Inflammasome activation by binding of ATP released from damaged cells to the purinergic receptor P2X7 (P2RX7) could play a role in hypertension and vascular injury through release of interleukin (IL)-1β and immune cell activation. Elevated ATP levels were observed in the renal interstitial fluid of angiotensin (Ang) II-infused rats, and treatment of these rats with a non-selective P2 receptor blocker prevented Ang II-induced inflammation and renal damage. P2RX7 knockout ( P2rx7 –/– ) prevented deoxycorticosterone acetate-salt-induced blood pressure (BP) elevation and renal damage. However, it is unknown whether P2RX7 plays a role in Ang II-induced BP elevation and vascular damage. We hypothesize that Ang II-induced hypertension, vascular injury, and inflammation will be blunted in P2rx7 -/- mice. Methods: Ten to 12-week-old male C57BL/6J male wild-type (WT) and P2rx7 –/– mice were sham-treated or infused with Ang II (490ng/kg/min) for 14 days. BP was determined by telemetry. Mesenteric artery function and remodeling was assessed using pressurized myography. P2RX7 expression in spleen immune cells was determined by flow cytometry. IL-1β secretion from bone marrow-derived macrophages (BMDM) isolated from WT and P2rx7 –/– mice was assessed by ELISA. Results: Stimulation with lipopolysaccharides and ATP caused IL-1β release in WT (339±162 pg/mL) but not P2rx7 –/– BMDMs. In WT mice, Ang II increased P2RX7 expression in dendritic cells (mean fluorescence intensity: 1927±120 vs 3983±983) and macrophages (2541±265 vs 3314±273 respectively). P2rx7 knockout reduced Ang II-induced systolic (159±3 vs 165±7 mm Hg) and diastolic BP elevation (110±4 vs 126 ±7 mm Hg) compared to WT mice. Acetylcholine-induced vascular relaxation was unaffected by Ang II or P2rx7 knockout. Ang II increased the media-to-lumen ratio in WT (4.71±0.18% vs 3.89±0.21%, P <0.01) but not in P2rx7 –/– mice. Conclusion: This study demonstrated that P2RX7 plays a role in Ang II-induced hypertension and vascular remodeling.