Leptin attenuates gene expression for renal 25-hydroxyvitamin D3-1α-hydroxylase in mice via the long form of the leptin receptor
Leptin attenuates gene expression for renal 25-hydroxyvitamin D3-1α-hydroxylase in mice via the long form of the leptin receptor
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DOI：
10.1016/j.abb.2007.02.031
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发表时间：
2007-07-01
影响因子：
3.9
通讯作者：
Horiuchi, Noboru
中科院分区：
文献类型：
--
作者：
Matsunuma, Ayako;Horiuchi, Noboru
瘦素是ob基因的产物，由脂肪细胞分泌，控制整体能量平衡。我们以前的研究表明，瘦素缺乏的肥胖（oblob）小鼠的瘦素管理抑制mRNA的表达和肾脏25-羟基维生素D-3-1 α-羟化酶（CYP 27 B1）的活性。在瘦素受体缺陷（db/db）小鼠中，我们目前研究瘦素是否通过活性形式的瘦素受体（ObRb）影响1 α-羟化酶在肾小管中的表达。在未治疗的oblob小鼠中，血清钙和1，25-二羟维生素D-3 [1，25-（OH）ZD（3）]浓度升高，瘦素给药（4 mg/kg，腹腔注射，每12小时一次，持续2天）后，血清钙和1，25-二羟维生素D-3 [1，25-（OH）ZD（3）]浓度急剧降低;在dbldb小鼠中，血清钙和1，25-（OH）ZD（3）浓度升高没有降低。ObRb mRNA在野生型和oblob小鼠的肾脏、脑、脂肪、肺和骨中表达，但在dbldb小鼠中不表达。oblob和dbldb小鼠显示肾la-羟化酶mRNA表达和活性大幅增加。瘦素给药（4 mg/kg）完全消除了oblob小鼠的这些增加，但没有dbldb小鼠。肾25-羟维生素D-3-24-羟化酶（CYP 24）mRNA的合成也大大提高了oblob和dbldb小鼠;过量的oblob小鼠瘦素管理显着下降，但增加dbldb小鼠。原代培养的肾小管细胞表达的mRNA包括近端小管标志物（1 α-羟化酶和巨蛋白）、甲状旁腺激素受体和维生素D受体。降钙素受体mRNA主要在远曲小管合成，表达量很少，表明培养的细胞主要来自近曲小管。细胞不表达ObRb mRNA。毛喉素暴露于10（-6）M 3或6 h显著增加1 α-羟化酶mRNA。在10-6 M的瘦素没有改变mRNA的表达在存在或不存在毛喉素。因此，瘦素通过ObRb减弱肾1 α-羟化酶基因表达。此外，瘦素似乎间接作用于肾近端小管以调节la-羟化酶基因表达。(c)2007年爱思唯尔公司All rights reserved.
Leptin, the ob gene product secreted by adipocytes, controls overall energy balance. We previously showed that leptin administration to leptin-deficient obese (oblob) mice suppressed mRNA expression and activity of renal 25-hydroxyvitamin D-3-1 alpha-hydroxylase (CYP27B1). In leptin receptor-deficient (db/db) mice, we presently examined whether leptin affects 1 alpha-hydroxylase expression in renal tubules through the active form of the leptin receptor (ObRb). Elevated serum concentrations of calcium and 1,25-dihydroxyvitamin D-3 [1,25-(OH)ZD(3)] in untreated oblob mice showed sharp reduction with leptin administration (4 mg/kg, i.p. every 12 h for 2 days); no such reduction of elevation occurred in dbldb mice. ObRb mRNA was expressed in kidney, brain, fat, lung, and bone in wild-type and oblob mice, but not dbldb mice. The oblob and dbldb mice showed large increases in renal la-hydroxylase mRNA expression and activity. Leptin administration (4 mg/kg) completely abrogated these increases in oblob but not dbldb mice. Renal 25-hydroxyvitamin D-3-24-hydroxylase (CYP24) mRNA synthesis also was greatly elevated in oblob and dbldb mice; excesses decreased significantly with leptin administration in oblob mice, but increased in dbldb mice. Renal tubular cells in primary culture expressed mRNAs including proximal tubules markers (1 alpha-hydroxylase and megalin), parathyroid hormone receptor, and vitamin D receptor. Calcitonin receptor mRNA, synthesized mainly in distal tubules, was scant, indicating that most cultured cells were from proximal tubules. Cells did not express ObRb mRNA. Forskolin exposure at 10(-6) M for 3 or 6 h significantly increased 1 alpha-hydroxylase mRNA. Leptin at 10-6 M did not change mRNA expression in either presence or absence of forskolin. Accordingly, leptin attenuates renal 1 alpha-hydroxylase gene expression through ObRb. Furthermore, leptin appears to act indirectly on renal proximal tubules to regulate la-hydroxylase gene expression. (c) 2007 Elsevier Inc. All rights reserved.