| [ Summary ] |
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. They function as ligand-inducible transcription factors. VDR is expressed in various organs such as bones or kidneys, and has many aspects related to physiological roles. Recently, we showed that 1,25-dihydroxyvitamin D3 [1,25(OH)2D]-bound VDR specifically inhibits TGF-β-Smad signal transduction through direct interaction with Smad3. TGF-β-Smad signal transduction, which is known to be involved in tissue fibrosis, including renal fibrosis. In mouse models, 1,25(OH)2D3 prevented renal fibrosis through the suppression of TGF-β-Smad signal transduction. Based on the structure of the VDR-ligand complex, we generated a synthetic ligand, DLAM-4P. DLAM-4P selectively inhibits TGF-β-Smad signal transduction without activating VDR-mediated transcription. It significantly attenuated renal fibrosis in mice. In addition, DLAM-4P did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. In relation to our study, a general method to develop synthetic ligands which stimulate specific nonclassical functions of nuclear receptors should be developed. Our findings may provide a paradigm for the development of drugs to treat various human diseases by specifically stimulating certain activities of nuclear receptors. |