Abstract
C57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). Here, we sought to characterize the development of CKD and its cardiac and skeletal sequelae during the first three months after 5/6-Nx in C57BL/6 mice fed a calcium- and phosphate enriched diet (CPD) with a balanced calcium/phosphate ratio. 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Interestingly, despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. A time course experiment revealed that 5/6-Nx mice on CPD developed progressive renal functional decline, renal fibrosis, cortical bone loss, impaired bone mineralization as well as hypertension, but not left ventricular hypertrophy. Collectively, our data show that the resistance of C57BL/6 mice to 5/6-Nx can be partially overcome by feeding the CPD, and that the CPD induces a profound, PTH-independent increase in FGF23 in 5/6-Nx mice, making it an interesting tool to assess the pathophysiological significance of FGF23 in CKD.
Highlights
C57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx)
To examine the potential disease-promoting effects of a calcium and phosphate-enriched diet (CPD) on 5/6-Nx-induced CKD in C57BL/6 mice, we performed a pilot experiment in which we compared the effects of calcium- and phosphate enriched diet (CPD) with a normal mouse chow on mineral homeostasis, kidney function, and cardiovascular function, 12 weeks postsurgery
Both serum calcium and serum phosphate were not influenced by the diet (Fig. 1b,c). 5/6-NX mice were characterized by hypercalcemia, but did not show hyperphosphatemia, 12 weeks postsurgery (Fig. 1b,c)
Summary
C57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. Chronic kidney disease (CKD) is characterized by a decrease in glomerular filtration rate (GFR). A plethora of studies have shown that cardiovascular diseases associated with CKD are the primary cause of death in patients, even before they reach end-stage renal d isease[1,2,3]. Low levels of the vitamin D hormone, as well as hyperphosphatemia induce parathyroid hormone (PTH) secretion This form of secondary hyperparathyroidism is partially responsible for the development of CKD-MBD11. FGF23 signaling has been directly linked to erythropoiesis and iron handling, further connecting CKD, MDB and cardiovascular d isease[8]
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