A nonclassical vitamin D receptor pathway suppresses renal fibrosis
A nonclassical vitamin D receptor pathway suppresses renal fibrosis
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DOI：
10.1172/jci67804
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发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Yanagisawa, Junn
中科院分区：
文献类型：
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作者：
Ito, Ichiaki;Waku, Tsuyoshi;Yanagisawa, Junn
tgf - β超家族包括调节SMAD和非SMAD信号的多效细胞因子。tgf - β - smad信号传递。我们知道，生产参与组织纤维化，包括肾纤维化。在这里，我们发现1,25-二羟基维生素D-3结合[1,25(OH)(2)D-3结合]维生素D受体（VDR）通过与SMAD3直接相互作用特异性抑制tgf - β - smad信号转导。在小鼠组织纤维化模型中，1,25 (OH)(2)D-3治疗通过抑制tgf - β - smad信号转导来预防肾纤维化。基于vdr -配体复合物的结构，我们合成了2个配体。这些配体选择性地抑制tgf - β - smad信号转导，而不激活vdr介导的转录，并显著减轻小鼠肾纤维化。这些结果表明，1,25(OH)(2) d -3依赖性tgf - β - smad信号转导的抑制与vdr介导的转录活性无关。此外，这些配体不会因刺激VDR的转录活性而引起高钙血症。因此，我们的研究为生成特异性抑制tgf - β - smad信号转导的化合物提供了一种新的策略。因为tgf - β - smad信号传输。据报道，催产素与几种疾病有关，我们的研究结果将有助于开发不会引起可检测到的副作用（如高钙血症）的新药。
The TGF-beta superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-beta-SMAD signal transd.uction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D-3-bound [1,25(OH)(2)D-3-bound] vitamin D receptor (VDR) specifically inhibits TGF-beta-SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25 (OH)(2)D-3 treatment prevented renal fibrosis through the suppression of TGF-beta-SMAD signal transd.uction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligand.s. These ligands selectively inhibited TGF-beta-SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)(2)D-3-dependent suppression of TGF-beta-SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-beta-SMAD signal transduction. Since TGF-beta-SMAD signal transd.uction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.