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

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 9

DLAM-iPr and DLAM-4P ameliorate folic acid–induced nephropathy.

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DLAM-iPr and DLAM-4P ameliorate folic acid–induced nephropathy. (A) DLAM...
(A) DLAM-iPr and DLAM-4P suppress the expression of profibrotic genes 129 days after folic acid injection. We prepared RNA from kidneys of mice treated with folic acid and the indicated ligands, and Cyp24a1, Serpine1, Acta2, and Col1a1 mRNA levels were examined by qPCR. (B) Representative photomicrographs of Masson’s trichrome staining (top row, whole kidney; second row, magnified view of boxed region, enlarged ×3.24), FSP-1– (third row), and α-SMA–specific immunofluorescence staining (bottom row) of kidney sections from mice that received folic acid (vehicle). 3 days after injection, mice were treated with vehicle, 0.6 μg/kg/d 1,25(OH)2D3, 60 μg/kg/d DLAM-iPr, or 60 μg/kg/d DLAM-4P by continuous infusion from osmotic pumps. Mice were analyzed 129 days after folic acid injection. Scale bars: 3.0 mm (top row); 500 μm (second row); 20 μm (bottom 2 rows). (C) Fibrotic area (n = 4 per group), FSP-1–positive cells in stained sections (n = 10 per group), and α-SMA–positive area (n = 10 per group). (D and E) Serum creatinine (D) and calcium (E) concentrations. Short-term, 14 days; Long-term, 129 days. *P < 0.05; **P < 0.01; ***P < 0.001.