High-phosphorus Diet Induces Upregulation Of Bmp2 And Spp1 MRNA Expression in Rat Kidney Ⅱ

Discussion 

One of the well-known physiological effects of a high-P diet is the development of nephrocalcinosis. In the present study, kidney Ca and P concentrations were increased in the high-P group compared to the control group, which is consistent with the results of previous studies1-6). Previous studies reported that histological scores of nephrocalcinosis were positively correlated with kidney Ca and P concentrations4, 21). Thus, although no histological observation of the kidney was carried out in the present study, increased kidney Ca and P concentrations indicate that nephrocalcinosis was induced by the high-P diet.

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Fig. 1 Renal mRNA expression of Bmp2 (A) and Spp1 (B) in control (open bar) and high-P (solid black bar) groups. The value of the control group was considered to be 1.00. Values are means ± SEM (n ＝ 6). * Significantly different from the control group (P ＜ 0.05).

Because Ca deposits induced by a high-P diet are generally thought to be a form of hydroxyapatite6, 7), we hypothesized that the development of nephrocalcinosis is controlled by a mechanism similar to that of osteogenesis. Thus, we examined the effects of a high-P diet on Bmp2 mRNA expression in the kidney. The results showed that renal Bmp2 mRNA expression was increased in the high-P group and that a high-P diet induces upregulation of Bmp2 mRNA expression in the kidney. This finding may help account for the mechanism of nephrocalcinosis development induced by high-P diet. Although definitive evidence supporting our hypothesis is lacking, one possibility is that the expression of osteogenic transcription factors is elevated in calcified regions in the kidney. BMP2 induces osteoblast differentiation and bone formation by regulating osteogenic transcription factors such as Osterix, Runx2, and Msx28, 9) ; thus, BMP2 may promote nephrocalcinosis via the regulation of such osteogenic transcription factors. At present, the detailed role of BMP2 in the development of nephrocalcinosis remains unclear. In addition, since only the Bmp2 mRNA expression was measured in this study, it is not known whether there is a difference in the BMP2 protein expression. However, our results suggest a possible mechanism by which alterations in BMP2 expression play a potent role in the pathogenesis of high-P diet-induced nephrocalcinosis.

The present study focused on Spp1 mRNA expression in addition to Bmp2 mRNA expression. Our previous study using immunohistochemical analysis indicated high levels of OPN expression in the renal tubules of rats fed a high-P diet12). The present study found that Spp1 mRNA expression was increased by approximately 10-fold in the high-P group. Results of the present and previous studies reveal that a high-P diet induces OPN expression in the kidney. On the other hand, other researchers have shown that OPN as a stone matrix is an important factor in the formation of urinary stones22, 23) ; thus, our previous report suggested that OPN may have a role as a matrix component in the formation of Ca deposits induced by a high-P diet12). However, Paloian et al. recently reported that OPN plays a role in the prevention of high-P diet-induced nephrocalcinosis in OPN KO mice24). Namely, the physiological role of OPN on high-P diet-induced nephrocalcinosis appears to be suppression rather than a promotion of calcification in the kidney. Moreover, previous reports is described that OPN levels increase to offset further pathologic ectopic calcification in the kidney and vasculature as OPN is upregulated at the site of pathologic calcification 24, 25).

As mentioned above, the present study suggested the importance of BMP2 and OPN in high-P diet-induced nephrocalcinosis. It is noteworthy that the effects of BMP2 and OPN on the development of nephrocalcinosis are thought to be regulated by different mechanisms. These mechanistic differences may indicate that the underlying mechanism of nephrocalcinosis is complicated.

The next point to consider is that growth inhibition may have affected Bmp2 and Spp1 mRNA expression in the kidney because the present study observed a reduction of final body weight in a high-P group. Observations in our previous12) and present studies may help account for this point. We previously reported increased OPN protein expression in renal tubules of rats whose growth was not inhibited by high-P diet12). Moreover, the present study showed growth inhibition in the high-P group, but high levels of Spp1 mRNA expression in the kidney. Based on these observations, the present study appears to have little effect of the growth inhibition on Bmp2 and Spp1 mRNA expression. However, the details of the relationship between growth inhibition and Bmp2 and Spp1 gene expression remain unclear. Therefore, further investigations are needed to elucidate this point. In conclusion, to clarify the mechanism of the development of nephrocalcinosis induced by a high-P diet, the present study determined the effects of a high-P diet on Bmp2 and Spp1 mRNA expression in the kidney. Kidney Ca and P concentrations were significantly increased in the high-P group compared to the control group. Further, mRNA expression of Bmp2 and Spp1 was significantly increased in the high-P group compared to the control group. These results indicate that a high-P diet promotes upregulation of Bmp2 and Spp1 mRNA expression in the kidney.

References  

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4) Cockell KA, L'Abbe MR, Belonje B: The concentrations and ratio of dietary calcium and phosphorus influence the development of nephrocalcinosis in female rats. J Nutr 132 : 252-256, 2002  

5) Katsumata S, Matsuzaki H, Uehara M, Suzuki K : Effects of dietary calcium supplementation on bone metabolism, kidney mineral concentrations, and kidney function in rats fed a high-phosphorus diet. J Nutr Sci Vitaminol 61 : 195-200, 2015  

6) Matsuzaki H, Uehara M, Suzuki K, Liu Q-L, Sato S, Kanke Y, Goto S : High phosphorus diet rapidly induces nephrocalcinosis and proximal tubular injury in rats. J Nutr Sci Vitaminol 43 : 627-641, 1997 

7) Liu Q-L, Sato S, Kishikawa T, Matsuzaki H, Yamanaka N : Effectiveness of traditional Chinese medicine, Wulingsan, in suppressing the development of nephrocalcinosis induced by a high phosphorus diet in young rats. Med Electron Microsc 34 : 103-114, 2001  

8) Sirard C, Kim S, Mirtsos C, Tadich P, Hoodless PA, Itie A, Maxson R, Wrana JL, Mak TW : Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor β-related signaling. J Biol Chem 275 : 2063-2070, 2000  

9) Matsubara T, Kida K, Yamaguchi A, Hata K, Ichida F, Meguro H, Aburatani H, Nishimura R, Yoneda T : BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem 283: 29119-29125, 2008

10) Urist MR : Bone: Formation by autoinduction. Science 150 : 893-899, 1965

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