A nonclassical vitamin D receptor pathway suppresses renal fibrosis

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

Research output: Contribution to journalArticle

80 Scopus citations

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)2D 3-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.

Original languageEnglish (US)
Pages (from-to)4579-4594
Number of pages16
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ito, I., Waku, T., Aoki, M., Abe, R., Nagai, Y., Watanabe, T., Nakajima, Y., Ohkido, I., Yokoyama, K., Miyachi, H., Shimizu, T., Murayama, A., Kishimoto, H., Nagasawa, K., & Yanagisawa, J. (2013). A nonclassical vitamin D receptor pathway suppresses renal fibrosis. Journal of Clinical Investigation, 123(11), 4579-4594. https://doi.org/10.1172/JCI67804