Journal Article

A nonclassical vitamin D receptor pathway suppresses renal fibrosis

Nagai, Yu, Murayama, Akiko, Ito, Ichiaki, Aoki, Masato, Ohkido, Ichiro, Abe, Rumi, Miyachi, Hiroyuki, Shimizu, Toshiyuki, Yanagisawa, Junn, Nakajima, Yuka, Watanabe, Tatsuya, Waku, Tsuyoshi, Kishimoto, Hiroyuki, Yokoyama, Keitaro, Nagasawa, Kazuo

2013

نظرة عامة

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.

• الناشر: American Society for Clinical Investigation
• موضوع: Acids / Alfacalcidol / Animals / Biomedical research / Calcifediol / Calcitriol - analogs & derivatives / Calcitriol - metabolism / Calcitriol - pharmacology / Care and treatment / Collagen / Crystal structure / Drug Discovery / Experiments / Fibrosis / Gene expression / Gene Knockdown Techniques / Genetic aspects / Genetic engineering / Health aspects / HEK293 Cells / Humans / Kidney - drug effects / Kidney - metabolism / Kidney - pathology / Kidneys / Laboratory animals / Lactams - pharmacology / Ligands / Metabolites / Mice / Mice, Inbred C57BL / Models, Molecular / Physiological aspects / Promoter Regions, Genetic / Proteins / Receptors, Calcitriol - antagonists & inhibitors / Receptors, Calcitriol - genetics / Receptors, Calcitriol - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Signal transduction / Signal Transduction - drug effects / Smad Proteins - metabolism / Studies / Transforming Growth Factor beta - metabolism / Transforming growth factors / Ureteral Obstruction - genetics / Ureteral Obstruction - metabolism / Ureteral Obstruction - pathology / Vitamin D