Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism
Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism
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DOI：
10.1007/s00424-014-1625-9
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发表时间：
2014-10
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影响因子：
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通讯作者：
Hajar Fahkri;Bingbing Zhang;Abul Fajol;N. Hernando;B. Elvira;J. Mannheim;B. Pichler;C. Daniel;K. Amann;A. Hirao;J. Haight;T. Mak;F. Lang;M. Föller
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文献类型：
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作者：
Hajar Fahkri;Bingbing Zhang;Abul Fajol;N. Hernando;B. Elvira;J. Mannheim;B. Pichler;C. Daniel;K. Amann;A. Hirao;J. Haight;T. Mak;F. Lang;M. Föller
检查点激酶2（Checkpoint kinase 2，Chk 2）是共济失调毛细血管扩张症突变型（ataxia telangiectasia mutated，ATM）的主要效应激酶，参与细胞周期调控。ATM信号已被证明上调干扰素调节因子-1（IRF-1），这是一种也在肾脏中表达的转录因子。骨化三醇（1，25（OH）2D 3）是矿物质代谢的主要调节剂，由肾脏中的25-羟基维生素D 1α-羟化酶产生。由于25-羟维生素D1 α-羟化酶的表达被IRF-1增强，本研究探讨了Chk 2在骨化三醇形成和矿物质代谢中的作用。将Chk 2缺陷小鼠（chk 2-/-）与野生型小鼠（chk 2 +/+）进行比较。通过RT-PCR测定肾脏25-羟基维生素D 1α-羟化酶、Chk 2和IRF-1的转录水平;通过蛋白质印迹法测定Klotho表达;通过μCT分析测定骨密度;通过免疫测定法测定血清或血浆1，25（OH）2D 3、PTH和C-末端FGF 23浓度;通过光度法测定血清、粪便和尿钙和磷酸盐浓度。与chk 2 +/+小鼠相比，chk 2 −/−小鼠的IRF-1和25-羟维生素D1 α-羟化酶的肾脏表达以及血清1，25（OH）2D 3和FGF 23水平显著较低。血浆PTH基因型之间没有差异。尽管存在低磷血症和正常钙血症，但inchk 2 −/−小鼠的肾钙和磷酸盐排泄量显著高于inchk 2 +/+小鼠。骨密度在基因型之间没有差异。我们得出结论，Chk 2调节肾脏25-羟维生素D1 α-羟化酶的表达，从而影响钙和磷代谢。
Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1α-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2−/−) were compared to wild-type mice (chk2+/+). Transcript levels of renal 25-hydroxyvitamin D 1α-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by μCT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1α-hydroxylase as well as serum 1,25 (OH)2D3and FGF23 levels were significantly lower inchk2−/−mice compared tochk2+/+mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher inchk2−/−mice than inchk2+/+mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression thereby impacting on calcium and phosphate metabolism.