title: 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.forename: Ichiaki
authors.initials: I
authors.lastname: Ito
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Waku
authors.forename: Masato
authors.initials: M
authors.lastname: Aoki
authors.forename: Rumi
authors.initials: R
authors.lastname: Abe
authors.forename: Yu
authors.initials: Y
authors.lastname: Nagai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ohkido
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Akiko
authors.initials: A
authors.lastname: Murayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Junn
authors.initials: J
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D055808:Drug Discovery; D005355:Fibrosis; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007769:Lactams / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C510297:DLAM-1P compound; D007769:Lactams; D008024:Ligands; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D002117:Calcitriol