Okamura Maro, Takano Yosuke, Saito Yukinori, Yao Jian, Kitamura Masanori
Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Nephrol Dial Transplant. 2009 Oct;24(10):3006-12. doi: 10.1093/ndt/gfp243. Epub 2009 May 27.
Nephrin is a key molecule involved in the structure and function of the slit diaphragm in the glomerulus. We previously reported that all-trans retinoic acid (ATRA) and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] induced expression of nephrin in murine podocytes. In this report, we investigated roles of the retinoic acid receptor (RAR), the retinoid X receptor (RXR) and the vitamin D receptor (VDR) in the regulation of the nephrin gene.
Reporter podocytes were treated with agonists and/or antagonists of RAR, RXR or VDR, and activities of the nephrin gene promoter, the retinoic acid response element (RARE) and the vitamin D response element (VDRE) were evaluated.
Expression of nephrin in podocytes was up-regulated by ATRA and 1,25(OH)(2)D(3). The nephrin gene promoter was also activated by these agents, which was mediated by RAR and VDR, but unexpectedly, not by RXR. ATRA-triggered, RAR-mediated activation of the nephrin gene promoter was not suppressed by the VDR antagonist. Similarly, ATRA-induced activation of RARE was not inhibited by the VDR antagonist. In contrast, the 1,25(OH)(2)D(3)-triggered, VDR-mediated activation of the nephrin gene promoter was significantly suppressed by the RAR antagonist, but not by RXR antagonists. Interestingly, 1,25(OH)(2)D(3)-induced activation of VDRE was not inhibited by the RAR antagonist.
These results suggested selective cooperation of RAR and VDR in the regulation of the nephrin gene, i.e. (1) ATRA induces nephrin gene expression via RAR independently of RXR and VDR and (2) 1,25(OH)(2)D(3) induces nephrin gene expression via selective cooperation of RAR and VDR, which is independent of RXR.
Nephrin是参与肾小球裂孔隔膜结构和功能的关键分子。我们之前报道过全反式维甲酸（ATRA）和1,25-二羟基维生素D3 [1,25(OH)2D3]可诱导小鼠足细胞中Nephrin的表达。在本报告中，我们研究了维甲酸受体（RAR）、类视黄醇X受体（RXR）和维生素D受体（VDR）在Nephrin基因调控中的作用。
用RAR、RXR或VDR的激动剂和/或拮抗剂处理报告基因足细胞，并评估Nephrin基因启动子、维甲酸反应元件（RARE）和维生素D反应元件（VDRE）的活性。
ATRA和1,25(OH)2D3可上调足细胞中Nephrin的表达。这些试剂也可激活Nephrin基因启动子，这是由RAR和VDR介导的，但出乎意料的是，不是由RXR介导。VDR拮抗剂不能抑制ATRA触发的、RAR介导的Nephrin基因启动子激活。同样，VDR拮抗剂也不能抑制ATRA诱导的RARE激活。相反，RAR拮抗剂可显著抑制1,25(OH)2D3触发的、VDR介导的Nephrin基因启动子激活，但RXR拮抗剂不能。有趣的是，RAR拮抗剂不能抑制1,25(OH)2D3诱导的VDRE激活。
这些结果表明RAR和VDR在Nephrin基因调控中存在选择性协同作用，即：（1）ATRA通过RAR诱导Nephrin基因表达，独立于RXR和VDR；（2）1,25(OH)2D3通过RAR和VDR的选择性协同作用诱导Nephrin基因表达，独立于RXR。
