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.

中文翻译：

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肾素原受体过度表达促进血管紧张素 II 诱导的载脂蛋白 E 基因敲除小鼠腹主动脉瘤形成。

肾素原受体 (PRR) 是肾素-血管紧张素 (Ang) 系统的重要新组分，具有多种功能，但尚未完全了解。在本研究中，我们旨在探讨 PRR 对载脂蛋白 E 敲除小鼠中 Ang II 诱导的腹主动脉瘤 (AAA) 形成的影响。我们使用 Ang II (1.44 mg/kg/天) 输注诱导 AAA，然后用盐水、替米沙坦、无治疗、Ad-EGFP、Ad-PRR 或 Ad-PRR 加替米沙坦进行治疗。在替米沙坦、赋形剂、Ad-EGFP、Ad-PRR 和 Ad-PRR+替米沙坦组中，AAA 的发生率分别为 35%、60%、65%、90% 和 55%。与Vehicle和Ad-EGFP组相比，PRR过表达显着增加巨噬细胞浸润；促炎细胞因子的水平，包括单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α）；MMP2和MMP9的表达和活性；NOX2和NOX4蛋白和mRNA表达；烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶活性；细胞外信号调节激酶 (ERK) 和 P38MAPK 表达；但降低了 AAA 中的平滑肌细胞含量。然而，替米沙坦逆转了 PRR 的不良反应。此外，ERK 抑制剂 PD98059 消除了 PRR 对 Ang II 诱导的 AAA 形成的加速，替米沙坦和 PD98059 的共同给药进一步消除了 PRR 对 Ang II 诱导的 AAA 形成的不利影响。因此，PRR 通过 ERK 通路的 Ang II 依赖性和 Ang II 非依赖性激活在 AAA 的病理发展中发挥重要作用。