Abstract 12397: BMP Type I Receptor Inhibition Reduces Endothelial Dysfunction and Vascular Osteogenic Differentiation in Mice With Chronic Kidney Disease
Background: Endothelial dysfunction and vascular calcification are characteristic features of vascular damage in 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, the mechanism underlying reduced eNOS phosphorylation in CKD is not defined. Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. The aim of this study was to examine the role of BMP type I receptor signaling in endothelial dysfunction and vascular osteogenic differentiation in CKD.
Methods and Results: CKD was created by performing 5/6 nephrectomy in C57BL/6 mice, which increased serum creatinine levels 2-fold without changing blood pressure (BP). Aortic strips from CKD mice showed impaired endothelium-dependent relaxation and reduced eNOS and Akt phosphorylations. Immunofluorescence staining of aortas from CKD mice showed that phosphorylated Smad1/5/8 was increased in the endothelial cells and medial vascular smooth muscle cells (VSMCs). To explore potential clinical interventions, we investigated the effects of LDN-193189 (LDN, 3 mg kg-1 i.p.), a small molecule inhibitor of BMP type I receptor kinases in CKD-induced endothelial dysfunction and VSMC osteogenic differentiation in mice. LDN administration did not affect renal function and BP. CKD-induced deterioration of endothelium-dependent relaxation was abolished by LDN treatment (Figure). In addition, VSMC osteogenic differentiation, indexed by alkaline phosphatase activity, was increased in medial VSMCs of CKD mice aortas, but not in those of CKD mice with LDN treatment.
Conclusions: BMP receptor-mediated signaling modulates CKD-induced endothelial dysfunction and VSMC osteogenic differentiation. Small molecule inhibitior of BMP type I receptor kinases may be useful for endothelial dysfunction and vascular calcification in CKD.
- © 2013 by American Heart Association, Inc.