Bone morphogenetic protein receptor activation plays a crucial role in endothelial dysfunction and osteogenic differentiation in mice with chronic kidney disease

Abstract

Background: Endothelial dysfunction and vascular calcification are the major cardiovascular complications in patients with chronic kidney disease (CKD). Recently, we showed that endothelial dysfunction is caused by reduced endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177 in CKD mice. However, little is known regarding the mechanisms of reduction of eNOS phosphorylation in CKD. Bone morphogenetic protein (BMP) receptor signaling is a key pathway of bone metabolism through Smad1/5/8 phosphorylation. The aim of this study was to examine the role of BMP receptor signaling in endothelial dysfunction and vascular osteogenic differentiation in CKD. Methods and results: We created a CKD model by performing 5/6 nephrectomy in wild-type (WT) mice, which increased serum creatinine levels 2-fold without changing blood pressure. WT mice with CKD (WT+CKD) showed impaired endothelium-dependent relaxation and reduced eNOS and Akt phosphorylations in the aorta. Immunohistostaining revealed that phosphorylated Smad1/5/8 was increased in the endothelial cells and medial vascular smooth muscle cells (VSMCs) of the aorta in WT+CKD mice. To investigate the causal relationship between BMP receptor activation and endothelial dysfunction, CKD was created in mice with heterozygous ablation of Alk3 (Alk3+/-), a BMP type 1 receptor. Basal and CKD-induced increases in serum creatinine levels were similar between WT and Alk3+/- mice. CKD-induced deterioration of endothelium-dependent relaxation and reduction of eNOS were abolished in Alk3+/- mice. In addition, alkaline phosphatase activity was increased in medial VSMCs of WT+CKD mice, but not in those of Alk3+/- +CKD mice. Conclusions: BMP receptor activation plays a crucial role in CKD-induced endothelial dysfunction and VSMC osteogenic differentiation. Thus, inhibition of BMP receptor signaling may be a therapeutic target for the prevention and treatment of endothelial dysfunction and vascular calcification in CKD patients.