A nonclassical vitamin D receptor pathway suppresses renal fibrosis

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.