Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells

被引:155
作者
Nii-Kono, T.
Iwasaki, Y.
Uchida, M.
Fujieda, A.
Hosokawa, A.
Motojima, M.
Yamato, H.
Kurokawa, K.
Fukagawa, M.
机构
[1] Kobe Univ, Sch Med, Div Nephrol, Chuo Ku, Kobe, Hyogo 6500017, Japan
[2] Kobe Univ, Sch Med, Dialysis Ctr, Kobe, Hyogo 6500017, Japan
[3] Oita Univ Nursing & Hlth Sci, Dept Hlth Sci, Oita, Japan
[4] KUREHA CORP Co Ltd, Tokyo, Japan
[5] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA
[6] Kureha Special Lab Co Ltd, Fukushima, Japan
[7] Univ Tokyo, Res Ctr Adv Sci, Div Hlth Policy, Tokyo, Japan
基金
日本学术振兴会;
关键词
D O I
10.1038/sj.ki.5002097
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 30,50 monophosphate ( cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter- 3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.
引用
收藏
页码:738 / 743
页数:6
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