BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease
BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease
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DOI：
10.1038/ki.2014.223
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发表时间：
2015-01-01
影响因子：
19.6
通讯作者：
Imaizumi, Tsutomu
中科院分区：
文献类型：
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作者：
Kajimoto, Hidemi;Kai, Hisashi;Imaizumi, Tsutomu
内皮功能障碍和血管钙化的分子机制被认为是独立的，目前尚不清楚慢性肾脏病（CKD）中的潜在联系。骨形态发生蛋白（BMP）受体信号介导动脉粥样硬化斑块钙化。在此，我们在短期CKD模型中检测BMP受体信号传导是否有助于内皮功能障碍以及血管平滑肌细胞（VSMC）的成骨分化。在C57 BL/6小鼠中，肾大部切除术激活了BMP受体，并增加了内皮细胞和中膜VSMC中的磷酸酶和张力蛋白同源物（PTEN）蛋白，而主动脉中没有血管重塑。在内皮细胞中，PTEN诱导导致Akt-内皮型一氧化氮合酶（eNOS）途径的抑制和内皮功能障碍。在VSMC中，PTEN的增加诱导早期成骨分化。CKD诱导的eNOS磷酸化抑制和由此产生的内皮功能障碍在内皮细胞特异性PTEN消融的小鼠中得到抑制。敲除BMP I型受体可消除CKD小鼠的内皮功能障碍、eNOS磷酸化抑制和VSMC成骨分化。BMP I型受体的小分子抑制剂LDN-193189可预防CKD小鼠的内皮功能障碍和成骨分化。因此，在短期CKD模型中，除了血管成骨分化之外，BMP受体活化是内皮功能障碍的机制。PTEN可能是连接BMP受体活化和CKD内皮功能障碍的关键。
The molecular mechanisms of endothelial dysfunction and vascular calcification have been considered independently and potential links are currently unknown in chronic kidney disease (CKD). Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. Here we tested whether BMP receptor signaling contributes to endothelial dysfunction, as well as to osteogenic differentiation of vascular smooth muscle cells (VSMCs), in a model of short-term CKD. In C57BL/6 mice, subtotal nephrectomy activated BMP receptor and increased phosphatase-and-tensin homolog (PTEN) protein in the endothelial cells and medial VSMCs without vascular remodeling in the aorta. In the endothelial cells, PTEN induction led to inhibition of the Akt-endothelial nitric oxide synthase (eNOS) pathway and endothelial dysfunction. In VSMCs, the PTEN increase induced early osteogenic differentiation. CKD-induced inhibition of eNOS phosphorylation and the resultant endothelial dysfunction were inhibited in mice with endothelial cell-specific PTEN ablation. Knockout of the BMP type I receptor abolished endothelial dysfunction, the inhibition of eNOS phosphorylation, and VSMC osteogenic differentiation in mice with CKD. A small molecule inhibitor of BMP type I receptor, LDN-193189, prevented endothelial dysfunction and osteogenic differentiation in CKD mice. Thus, BMP receptor activation is a mechanism for endothelial dysfunction in addition to vascular osteogenic differentiation in a short-term CKD model. PTEN may be key in linking BMP receptor activation and endothelial dysfunction in CKD.