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 D 3 -bound [1,25(OH) 2 D 3 -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) 2 D 3 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) 2 D 3 -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.

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

“…In particular, vitamin D receptor signaling prevents CCl4-induced liver fibrosis, inhibiting SMAD3 occupancy and SMAD-dependent transcriptional activity (56). Furthermore, vitamin D receptor agonists without hypercalcemic effects showed antifibrotic activity (57). This serves as a proof of concept that development of nuclear receptor ligands capable of disrupting TGF-β/SMAD activity could constitute a novel pharmacological approach to treat human diseases.…”

Vitamin D receptor regulates TGF-β signalling in systemic sclerosis

“…Indeed, VDR agonists have recently been shown to prevent activation of hepatic stellate cells in liver cirrhosis and epithelial-to-mesenchymal transition in kidney fibrosis. [47][48][49][50] VDR agonists may also modulate the outcome of fibrotic diseases by regulating T cell differentiation and B cell activation. 6 Although further studies in additional model systems are required, our findings have direct translational implications because paricalcitol is approved for clinical use.…”

Untitled

“…There is ample mechanistic understanding of the antifibrotic actions of vitamin D, including the following: (1) suppression of the renin-angiotensin and nuclear factor κB systems, 8,37,38 (2) increased expression of hepatocyte growth factor, 39 (3) direct repression of collagen I expression, 40 and (4) interference with transforming growth factor-betapromoted activation of fibrogenic genes by direct dislodging by activated vitamin D receptor complexes of SMAD3 binding to its DNA-binding elements. 41,42 We postulate that the clear decrease in fibrosis elicited by 2AMD and 2MD will lead to frank improvement in renal function with extended therapy. Based on our results and the literature described here, further investigations of vitamin D and its noncalcemic analogs as potential therapeutics in the small molecule tool box of antifibrotics 43 are warranted, with future conclusive testing in randomized clinical trials for the prevention and treatment of fibrosis associated with graft failure in transplanted kidneys.…”