Dexamethasone differentially regulates renal and duodenal calcium-processing genes in calbindin-D9k and -D28k knockout mice
Dexamethasone differentially regulates renal and duodenal calcium-processing genes in calbindin-D9k and -D28k knockout mice
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DOI：
10.1113/expphysiol.2008.044339
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发表时间：
2009-01-01
影响因子：
2.7
通讯作者：
Jeung, Eui-Bae
中科院分区：
文献类型：
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作者：
Kim, Man-Hee;Lee, Geun-Shik;Jeung, Eui-Bae
糖皮质激素（GC）似乎下调十二指肠中的活性钙转运基因，导致GC诱导的钙吸收障碍。在这项研究中，我们研究了GCs对十二指肠和肾脏钙加工基因的影响以及钙结合蛋白-D9 k（CaBP-9 k）和钙结合蛋白-D28 k（CaBP-28 k）敲除（KO）小鼠的代偿机制。在十二指肠中，我们观察到钙结合蛋白基因敲除小鼠和CaBP-28 k基因敲除小鼠的瞬时受体电位香草酸6（TRPV 6）mRNA和CaBP-9 k转录物的代偿性增加，并且通过添加合成GC地塞米松（Dex，10 mg kg（-1））降低其表达。此外，质膜钙ATP酶1b（PMCA 1b）的表达在CaBP-9 k KO小鼠中经历了代偿性增加，并被Dex阻断，而十二指肠钠钙交换器1的mRNA水平不受KO状态或Dex的影响。CaBP-9 k KO小鼠和CaBP-28 k KO小鼠肾脏中TRPV 5和CaBP-9 k的转录水平以补偿方式上调，而CaBP-28 k KO小鼠肾脏中Dex处理后TRPV 6基因下调。这些十二指肠蛋白作为Dex参与调节的主要靶点的免疫学位置不受Dex或KO状态的改变。为了阐明Dex诱导的代偿性基因表达的潜在机制，还测量了这些组织中GC受体（GR）、维生素D受体（VDR）和甲状旁腺激素受体（PTHR）mRNA的水平。在两种类型的KO小鼠中，十二指肠VDR转录物均以代偿性方式诱导，并被Dex降低。此外，两种KO小鼠的血清皮质酮水平均低于野生型小鼠。总之，这些结果表明，十二指肠TRPV 6和CaBP-9 k基因似乎是GC诱导的钙吸收障碍的主要目标，通过直接调节十二指肠VDR转录。
Glucocorticoids (GCs) appear to downregulate active calcium-transporting genes in the duodenum, resulting in GC-induced calcium-absorbing disorder. In this study, we examined the effects of GCs on calcium-processing genes in the duodenum and kidney and the compensatory mechanism in calbindin-D9k (CaBP-9k) and calbindin-D28k (CaBP-28k) knockout (KO) mice. In the duodenum, we observed compensatory increases in transient receptor potential vanilloid 6 (TRPV6) mRNAs in both calbindin KO mice and CaBP-9k transcripts in CaBP-28k KO mice, and their expressions were decreased by addition of a synthetic GC, dexamethasone (Dex, 10 mg kg(-1)). In addition, the expression of plasma membrane calcium ATPase 1b (PMCA1b) underwent a compensatory increase in CaBP-9k KO mice, and was blocked by Dex, while the mRNA level of duodenal sodium-calcium exchanger 1 was not altered by KO status or Dex. The renal transcriptional levels of TRPV5 in CaBP-9k KO and CaBP-9k in CaBP-28k KO mice were upregulated in a compensatory manner, while the TRPV6 gene was downregulated following treatment with Dex in the kidney of CaBP-28k KO mice. The immunological location of these duodenal proteins as a primary target of Dex-involved regulation was not altered by Dex or KO status. To elucidate potential mechanism(s) of Dex-induced compensatory gene expression, the levels of GC receptor (GR), vitamin D receptor (VDR) and parathyroid hormone receptor (PTHR) mRNA was also measured in these tissues. Duodenal VDR transcripts were induced in a compensatory manner in both types of KO mice, and were decreased by Dex. In addition, serum corticosterone levels in both KO mice were lower than in wild-type mice. In conclusion, these results suggest that duodenal TRPV6 and CaBP-9k genes appear to be a primary target for GC-induced calcium-absorbing disorder, through direct regulation of duodenal VDR transcription.