Pro-Renin Receptor Overexpression Promotes Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-Knockout Mice

Abstract

The pro-renin receptor (PRR) is an important novel component of the renin–angiotensin (Ang) system that has multiple functions, which are not yet completely understood. In this study, we aimed to explore the effect of PRR on the formation of Ang II–induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II (1.44 mg/kg/day) infusion to induce AAA followed by a treatment of saline, telmisartan, no treatment, Ad-EGFP, Ad-PRR, or Ad-PRR plus telmisartan. The incidence of AAA was 35%, 60%, 65%, 90%, and 55% in the Telmisartan, Vehicle, Ad-EGFP, Ad-PRR, and Ad-PRR+Telmisartan groups, respectively. Compared with the Vehicle and Ad-EGFP groups, PRR overexpression markedly increased macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α); the expression and activity of MMP2 and MMP9; NOX2 and NOX4 protein and mRNA expression; nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity; extracellular-signal-regulated kinase (ERK) and P38MAPK expression; but decreased smooth muscle cells content in AAA. However, telmisartan reversed the adverse effects of PRR. In addition, ERK inhibitor PD98059 eliminated the acceleration of Ang II–induced AAA formation by PRR, and coadministration of telmisartan and PD98059 further abolished the adverse effects of PRR on Ang II–induced AAA formation. Thus, PRR plays an important role in the pathological development of AAA via both Ang II–dependent and Ang II–independent activation of ERK pathways. These results suggest that inhibition of PRR activation may be a promising approach to the treatment of AAA.