Abstract
Medial arterial calcification (MAC) and renal osteodystrophy are complications of mineral bone disease (MBD) associated with chronic kidney disease (CKD). Our aim was to develop a novel mouse model to investigate the clinical course of CKD-MBD. Eight-week-old C57BL/6 J male mice were assigned to the following groups: the control group, fed a standard chow for 6 or 12 weeks; the CKD-normal phosphorus (NP) group, fed a chow containing 0.2% adenine, with normal (0.8%) phosphorus, for 6 or 12 weeks; and the CKD-high phosphorus (HP) group, fed 6 weeks with the 0.2% adenine/0.8% phosphorus diet, followed by a chow with 1.8% phosphorus for 2 weeks, 4 weeks or 6 weeks. Serum phosphorus was significantly increased in the CKD-HP group, and associated with MAC formation; the volume of calcification increased with longer exposure to the high phosphorus feed. MAC was associated with upregulated expression of runt-related transcription factor 2, alkaline phosphatase, and osteopontin, indicative of osteoblastic trans-differentiation of vascular smooth muscle cells. A significant mineral density depletion of cortical bone was observed. We describe the feasibility of developing a model of CKD-MBD and provide findings of a direct association between elevated serum phosphorus and the formation of MAC and renal osteodystrophy.
Highlights
The prevalence of chronic kidney disease (CKD) has increased as a function of the global aging of our society and the increasing prevalence of life-style related disease
C57BL/6J male mice were randomly allocated to the following experimental groups: control groups C6 and C12, and CKD group containing two CKD plus normal phosphorus (CKD-NP) groups (A6 and A12) and the CKD plus high phosphorus (CKD-HP) group which was subdivided into A6P2, A6P4, and A6P6 as described thoroughly in the material and methods (Fig. 1)
Our results aligned with a previous report by Jia et al of an increase in intact parathyroid hormone (PTH) and FGF-23 rose with a prolonged administration of an adenine-containing diet[35]
Summary
The prevalence of chronic kidney disease (CKD) has increased as a function of the global aging of our society and the increasing prevalence of life-style related disease. MAC leads to a reduced compliance of the walls of arteries, resulting in an increase in pulse-wave velocity and systolic pressure Over time, these altered mechanical and hemodynamic properties lead to left ventricular hypertrophy, decreased coronary perfusion, and heart failure[6, 10]. The risk for MAC-related complications increases as the stage of CKD advances[13], with various factors associated with the formation of MAC in patients with CKD14. Such factors include elevated levels of serum phosphorus, calcium, parathyroid hormone (PTH), and indoxyl sulfate; and decreased levels of vasoprotective agents, pyrophosphate (PPi), fetuin A, and matrix gla-protein (MGP). MAC does not consistently develop over time in the adenine mouse model[35] as the C57BL/6J mouse strain, which is typically used, is quite tolerant to ectopic calcification[42]
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