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Updated: May 6, 2026

Identification of the Source of Secreted Proteins in the Kidney by Brefeldin A Injection
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Identification of the Source of Secreted Proteins in the Kidney by Brefeldin A Injection

Published on: November 10, 2021

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A nonclassical vitamin D receptor pathway suppresses renal fibrosis

Ichiaki Ito, Tsuyoshi Waku, Masato Aoki

    The Journal of Clinical Investigation
    |October 19, 2013
    PubMed

    Insights

    Vitamin D receptor (VDR) activation by 1,25-dihydroxyvitamin D3 inhibits kidney fibrosis by blocking TGF-β-SMAD signaling. Novel synthetic ligands selectively target this pathway, offering potential treatments for fibrotic diseases without adverse effects.

    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Pharmacology

    Background:

    • The transforming growth factor-beta (TGF-β) superfamily regulates cellular processes via SMAD and non-SMAD signaling pathways.
    • TGF-β-SMAD signal transduction is implicated in the pathogenesis of tissue fibrosis, particularly renal fibrosis.

    Purpose of the Study:

    • To investigate the inhibitory effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on TGF-β-SMAD signal transduction.
    • To develop novel synthetic ligands that selectively inhibit TGF-β-SMAD signaling for potential therapeutic applications in fibrotic diseases.

    Main Methods:

    • Studied the interaction between 1,25(OH)2D3-bound vitamin D receptor (VDR) and SMAD3.
    • Utilized mouse models of renal fibrosis to evaluate the efficacy of 1,25(OH)2D3 and synthetic VDR ligands.
    • Designed synthetic ligands based on the VDR-ligand complex structure.

    Main Results:

    • 1,25(OH)2D3-bound VDR directly interacts with SMAD3, inhibiting TGF-β-SMAD signal transduction.
    • 1,25(OH)2D3 treatment attenuated renal fibrosis in mouse models by suppressing TGF-β-SMAD signaling.
    • Generated synthetic ligands selectively inhibited TGF-β-SMAD signaling without VDR transcriptional activation, reducing renal fibrosis and avoiding hypercalcemia.

    Conclusions:

    • 1,25(OH)2D3-mediated suppression of TGF-β-SMAD signaling is independent of VDR transcriptional activity.
    • Novel synthetic ligands offer a targeted approach to inhibit TGF-β-SMAD signaling, presenting a promising therapeutic strategy for fibrotic disorders with reduced adverse effects like hypercalcemia.

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