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A nonclassical vitamin D receptor pathway suppresses renal fibrosis
Ichiaki Ito, … , Kazuo Nagasawa, Junn Yanagisawa
Ichiaki Ito, … , Kazuo Nagasawa, Junn Yanagisawa
Published October 25, 2013
Citation Information: J Clin Invest. 2013;123(11):4579-4594. https://doi.org/10.1172/JCI67804.
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Research Article

A nonclassical vitamin D receptor pathway suppresses renal fibrosis

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Abstract

The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β–SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3–bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β–SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β–SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β–SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β–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-β–SMAD signal transduction. Since TGF-β–SMAD signal transduction 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.

Authors

Ichiaki Ito, Tsuyoshi Waku, Masato Aoki, Rumi Abe, Yu Nagai, Tatsuya Watanabe, Yuka Nakajima, Ichiro Ohkido, Keitaro Yokoyama, Hiroyuki Miyachi, Toshiyuki Shimizu, Akiko Murayama, Hiroyuki Kishimoto, Kazuo Nagasawa, Junn Yanagisawa

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Figure 6

DLAM derivatives that suppress TGF-β–dependent transcription without VDR transactivation.

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DLAM derivatives that suppress TGF-β–dependent transcription without VDR...
(A) DLAM derivatives, DLAM-iPr and DLAM-4P, used in this study. (B) Binding of DLAM-iPr and DLAM-4P to agonistic VDR. The DLAM derivatives were docked into the ligand-binding pocket in the VDR-LBD complexed with 1,25(OH)2D3 (PDB: 1DB1) using MOE. The ligand-binding pocket of VDR-LBD-ΔH12 is represented as a mesh model. (C) Dose responses of DLAM-iPr and DLAM-4P. Plasmids encoding ALK5 TD and VDR were transfected with reporter plasmids VDRE-Luc and CAGA-Luc into HEK293 cells. After culturing transfected cells with or without 1,25(OH)2D3 (10 nM), 1,25-lactone (0.01, 0.1, or 1 μM), or DLAM derivatives (0.01, 0.1, or 1 μM) for 24 hours, cell extracts were analyzed in luciferase assays. (D) TCMK-1 cells were cultured in the presence or absence of 5 ng/ml TGF-β and 10 nM 1,25(OH)2D3, 1 μM DLAM-iPr, or 1 μM DLAM-4P. Cyp24a1, Serpine1, and Acta2 mRNA levels were determined using qPCR. (E) Kidney fibroblasts were isolated and cultured in the presence or absence of 5 ng/ml TGF-β and 10 nM 1,25(OH)2D3, 1 μM DLAM-iPr, or 1 μM DLAM-4P for 8 hours, and Cyp24a1, Serpine1, Acta2, and Col1a1 mRNA levels were determined using qPCR. *P < 0.05; **P < 0.01; ***P < 0.001.

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