Loss of vitamin D receptor in chronic kidney disease: a potential mechanism linking inflammation to epithelial-to-mesenchymal transition.
Both peritubular inflammation and tubular epithelial-to-mesenchymal transition (EMT) are critical events during the pathogenesis of renal fibrosis. However, the relationship between these two processes is unclear. Here, we investigated the potential role of the vitamin D receptor (VDR) in coupling peritubular inflammation and EMT. In a mouse model of unilateral ureteral obstruction (UUO), loss of VDR was observed as early as 1 day after surgery. In cultured proximal tubular epithelial HK-2 cells, proinflammatory TNF-α inhibited the expression of VDR in a dose- and time-dependant manner. Treatment with TNF-α sensitized HK-2 cells to EMT stimulated by transforming growth factor (TGF)-β1. Ectopic expression of VDR counteracted the synergistic effect of TNF-α and TGF-β1 on EMT. Furthermore, knockdown of VDR using a small interfering RNA strategy mimicked the effect of TNF-α on facilitating EMT. Either TNF-α treatment or a loss of VDR induced β-catenin activation and its nuclear translocation. The VDR ligand calcitriol reversed the VDR loss and inhibited EMT in the mouse UUO model, and late administration of active vitamin D was effective in restoring VDR expression as well, and reduced collagen accumulation and deposition compared with the vehicle control. β-Catenin expression induced by UUO was also significantly inhibited after the late administration of vitamin D. These results indicate that the early loss of VDR in chronic kidney diseases was likely mediated by proinflammatory TNF-α, which renders tubular cells susceptible to EMT. Our data suggest that loss of VDR couples peritubular inflammation and EMT, two key events in renal fibrogenesis.
Dept. of Pathology, Nankai Univ., Medical School, R116 Medical School Bldg., 94 Weijin Rd., Nankai District, Tianjin, 300071 China. xiaoyuetan@nankai.edu.cn
Min
M
Xiong
Junbo
J
Gong
Youhua
Y
Liu
Rong
R
Xiang
Xiaoyue
X
Tan
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D018167:Receptors, Calcitriol; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin