High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression
Introduction
Bone and mineral disorders caused by chronic kidney disease (CKD), particularly by the related poor control of hyperphosphatemia, have been linked to the increased risk of vascular calcification [1], [2]. In addition, the latter has been described as one of the main drivers of mortality in CKD patients [3], [4].
Vascular calcification occurs trough a complex mechanism [5] that consists not only in a simple deposition of calcium and phosphate, but also in a regulated process similar to bone formation which involves loss of vascular calcification inhibitors [6], formation of calcification vesicles [7], and cellular phenotypic changes from vascular smooth muscle cells (VSMCs) to bone-like cells [8]. These new “vascular osteoblasts” are able to express bone-related genes and proteins, such as alkaline phosphatase, Cbfa1/Runx2, osteopontin, osteoprotegerin (OPG) and Msx2, among others [9]. In addition, in the general population and also in CKD patients, the rate and progression of vascular calcification have been associated with an increased risk of bone loss and osteoporotic fractures [10], [11], involving several but not fully understood genetic and molecular mechanisms.
The present experimental study was designed to prospectively assess the effects of high phosphorus diet on bone mass and vascular calcification, while paying attention to the gene expression profile of the arterial wall.
Section snippets
Animal model
The study was performed using 4-month-old male Wistar rats (n = 70). The rats were anaesthetized using methoxi-fluorane, and chronic renal failure (CRF) was induced by surgical 7/8 nephrectomy using the technique modified by Ormrod and Miller [12] by the same technician for all the groups. The nephrectomized rats were subsequently divided in two groups: Group I was fed with normal phosphorus diet (NPD) (0.6% phosphorus, 0.6% calcium and 20% protein content), and group II was fed with high
Biochemical markers
Serum phosphorus and iPTH levels were significantly higher (p < 0.05) in all high phosphorus diet (HPD) groups compared to the paired normal phosphorus diet (NPD) groups. In addition, in the HPD groups, both serum phosphorus and iPTH increased over-time. Conversely, serum calcium was lower in the HPD groups compared to the paired NPD groups, achieving statistically significant differences in the 8HPD and 20HPD groups (Table 1).
All groups showed a reduction in renal function compared to the
Discussion
Vascular calcification, bone loss, increased fractures and high risk of mortality are severe and threatening outcomes in the CKD population at all stages [10], [19], [20], [21]. The importance of all these factors has been recently stressed and also recognized by K-DIGO with the a new nomenclature for all bone mineral disorders associated to CKD [22]. Elevated serum phosphorus has been described as one of the main pathogenetic players for all these abnormalities [2], [23], particularly in the
Acknowledgments
The authors wish to thank Dr. Socorro Braga and Dr. Teresa Fernández-Coto for their assistance in the biochemical analyses, Vanessa Loredo for her help with the TRAP staining in methacrylate sections and Daniel Álvarez-Hernández, Ángeles González-Carcedo and specially Ana Rodríguez-Rebollar for the valuable help with the animals, von Kossa and densitometric analysis. We also thank Marino Santirso for the language review.
Disclosure: This work was supported by Fondo de Investigaciones Sanitarias
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