Abstract
Background This study explored the changes in expression of vascular smooth muscle cell (VSMC) markers and osteogenic markers, as well as the involvement of Notch1-RBP-Jk/Msx2 pathway in a rat model of diabetic nephropathy (DN) with vascular calcification. Methods A rat model of DN with concomitant vascular calcification was created by intraperitoneal injection of streptozotocin followed by administration of vitamin D3 and nicotine. Biochemical analysis and histological examination of aortic tissue were performed. VSMC markers and osteogenic markers as well as target molecules in Notch1-RBP-Jk/Msx2 were determined by quantitative real-time polymerase chain reaction and immunohistochemical analysis. Results Serum calcium and phosphorus levels were significantly increased in model rats as compared to that in normal controls. Diabetic rats with vascular calcification exhibited mineral deposits in aortic intima-media accompanied by decreased expression of VSMC markers and increased expression of osteogenic markers. Notch1, RBP-Jk, Msx2, Jagged1, and N1-ICD were barely expressed in the aortic wall of normal rats. In contrast, these were significantly increased in the model group at all time points (8, 12, and 16 weeks), as compared to that in the normal rats. Conclusion Activation of the Notch1-RBP-Jk/Msx2 signaling pathway may be involved in the development and progression of vascular calcification in DN.
Highlights
Vascular calcification is a key pathological process that contributes to cardiovascular complications of chronic kidney disease (CKD) and is an independent risk factor for cardiovascular events and mortality in patients with CKD [1, 2]
Intramuscular injection of vitamin D3 and/or intragastric administration of nicotine are commonly used to establish a rat model of vascular calcification [14, 16, 17]
The combination of vitamin D3 and nicotine leads to a substantial increase in calcium content of the aorta in rats [16]
Summary
Vascular calcification is a key pathological process that contributes to cardiovascular complications of chronic kidney disease (CKD) and is an independent risk factor for cardiovascular events and mortality in patients with CKD [1, 2]. Vascular calcification is a complex, irreversible biological process, which involves differentiation of vascular smooth muscle cells (VSMCs) into chondrocyte- or osteoblast-like cells (chondrogenesis or osteogenesis) It is accompanied by downregulation of contractile VSMC markers, such as alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α), and upregulation of various osteogenic transcription factors, such as runt-related transcription factor 2 (Runx2), Msx, alkaline phosphatase (ALP), osteopontin (OPN), and bone morphogenetic protein 2 (BMP2) [5,6,7,8]. This study explored the changes in expression of vascular smooth muscle cell (VSMC) markers and osteogenic markers, as well as the involvement of Notch1-RBP-Jk/Msx pathway in a rat model of diabetic nephropathy (DN) with vascular calcification.
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