High-dose vitamin D3 supplementation ameliorates renal fibrosis by vitamin D receptor activation and inhibiting TGF-β1/Smad3 signaling pathway in 5/6 nephrectomized rats.

Renal fibrosis is the pathological consequence of progressive chronic kidney disease. Although it has been reported that vitamin D3 exerts antifibrotic effects, the underlying mechanisms remain unclear. This study is aimed at investigating the effects and molecular mechanisms in high-dose vitamin D3 treatment on renal fibrosis. A model of chronic kidney disease was established by 5/6 nephrectomy in rats characterised by high levels of serum creatine, urea nitrogen, and urinary protein. Serum 25-dihydroxyvitamin D3, calcium and parathormone levels were measured to evaluate vitamin D levels. Hematoxylin and eosin, periodic acid Schiff and Mallory's Trichrome staining were used to evaluate histopathological changes in rats. Moreover, the expression of vimentin, collagen I, α-smooth muscle actin and E-cadherin were analyzed at molecular and histopathological levels. Our results showed that exposure to vitamin D3 decreased the levels of serum creatine, urea nitrogen and urine protein and restored the homeostasis of calcium and parathormone. Vitamin D3 also downregulated the expression of vimentin, collagen I and α-smooth muscle actin and attenuated renal fibrosis and epithelial to mesenchymal transition in the kidney. Importantly, vitamin D3 treatment increased the expression of the vitamin D receptor and inhibited Transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway in rats kidneys with chronic kidney disease. Mechanistically, the upregulation of TGF-β1 and phosphorylation of Smad3 induced by vitamin D3 was reversed by activation of the vitamin D receptor. Our findings indicated that vitamin D3 is a potential antifibrotic drug in chronic kidney disease via the vitmin D receptor and inhibiting TGF-β1/Smad3 signaling pathway.