BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease.

Hidemi Kajimoto, Hisashi Kai, Hiroki Aoki, Hiroki Uchiwa, Yuji Aoki, Suguru Yasuoka, Takahiro Anegawa, Yuji Mishina, Akira Suzuki, Yoshihiro Fukumoto, Tsutomu Imaizumi

Kidney international 2015 Jan

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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.

Citation

Hidemi Kajimoto, Hisashi Kai, Hiroki Aoki, Hiroki Uchiwa, Yuji Aoki, Suguru Yasuoka, Takahiro Anegawa, Yuji Mishina, Akira Suzuki, Yoshihiro Fukumoto, Tsutomu Imaizumi. BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease. Kidney international. 2015 Jan;87(1):128-36