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BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease
Hidemi Kajimoto1, Hisashi Kai1, Hiroki Aoki2
1Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
Insights
Bone morphogenetic protein (BMP) receptor signaling drives endothelial dysfunction and vascular calcification in chronic kidney disease (CKD). Targeting BMP receptor signaling may offer new therapeutic strategies for CKD patients.
Area of Science:
- Cardiovascular Biology
- Nephrology
- Molecular Medicine
Background:
- Endothelial dysfunction and vascular calcification are key complications in chronic kidney disease (CKD), but their molecular links remain unclear.
- Bone morphogenetic protein (BMP) receptor signaling is known to mediate vascular calcification.
- This study investigates the role of BMP receptor signaling in endothelial dysfunction within a CKD context.
Purpose of the Study:
- To determine if BMP receptor signaling contributes to endothelial dysfunction and vascular smooth muscle cell (VSMC) osteogenic differentiation in a short-term CKD model.
- To elucidate the molecular mechanisms linking BMP receptor activation to endothelial dysfunction in CKD.
- To assess the therapeutic potential of inhibiting BMP receptor signaling in CKD.
Main Methods:
- Utilized a subtotal nephrectomy model of short-term chronic kidney disease (CKD) in C57BL/6 mice.
- Investigated the activation of BMP receptor signaling and phosphatase and tensin homolog (PTEN) protein levels in aortic endothelial cells and VSMCs.
- Employed endothelial cell-specific PTEN ablation and BMP type I receptor knockout mouse models.
- Administered a small molecule inhibitor of BMP type I receptor (LDN-193189).
Main Results:
- Subtotal nephrectomy activated BMP receptor signaling and increased PTEN in endothelial cells and VSMCs, leading to endothelial dysfunction via the Akt-eNOS pathway.
- Increased PTEN in VSMCs promoted early osteogenic differentiation.
- Endothelial dysfunction and VSMC osteogenic differentiation were ameliorated by PTEN ablation and BMP type I receptor knockout.
- LDN-193189 treatment prevented endothelial dysfunction and osteogenic differentiation in CKD mice.
Conclusions:
- BMP receptor activation is a significant mechanism underlying endothelial dysfunction and vascular osteogenic differentiation in short-term CKD.
- PTEN acts as a crucial mediator, linking BMP receptor activation to endothelial dysfunction in the CKD model.
- Inhibition of BMP receptor signaling demonstrates therapeutic potential for mitigating vascular complications in CKD.
Abstract:
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.
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