Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Japan; Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, Graduate School of Medicine, Tohon, Japan.
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, Japan.
Kidney Int. 2019 Jan;95(1):138-148. doi: 10.1016/j.kint.2018.07.028. Epub 2018 Nov 12.
Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-γ, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-γ antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.
血管钙化是动脉粥样硬化和慢性肾脏病患者的常见现象。肾素-血管紧张素系统在心血管重构的发病机制中发挥作用。在这里，我们检验了这样一个假设，即血管紧张素 II 型受体（AT2）的刺激对磷酸盐诱导的血管钙化具有抑制作用。在体内，与野生型和 AT2 基因敲除型（AT2KO）小鼠相比，腺嘌呤和高磷饮食诱导的胸主动脉钙化在平滑肌细胞特异性 AT2 过表达小鼠（smAT2-Tg）中明显减弱。同样，smAT2-Tg 小鼠的相关成骨和血管平滑肌细胞标记基因的 mRNA 水平没有变化，而在野生型小鼠中，这些基因的表达在高膳食磷酸盐的刺激下明显改变。在体外，胸主动脉切片在补充无机磷酸盐的培养基中培养。与野生型小鼠相比，smAT2-Tg 小鼠的主动脉环显示出较少的血管钙化。在体外，与另外两组小鼠相比，源自 smAT2-Tg 小鼠的原代血管平滑肌细胞中由高磷介质诱导的钙沉积明显减少。为了评估潜在的机制，我们研究了 PPAR-γ 的作用，我们之前报道过它是 AT2 刺激的可能下游效应器之一。用 PPAR-γ 拮抗剂处理可减弱在喂食腺嘌呤和高磷饮食的 smAT2-Tg 小鼠中观察到的对血管钙化的抑制作用。我们的结果表明，AT2 激活代表了一种针对血管钙化的内源性保护途径。其刺激可能有效地减少慢性肾脏病患者的不良心血管事件。
