In vivo studies show that active vitamin D preserves the integrity of tubular epithelium by restoring E-cadherin and VDR expression in obstructive nephropathy [6
], consistent with its pro-differentiation potential. In the fibrotic kidney after sustained injury, tubular epithelial cells undergo a phenotypic transition known as EMT to become myofibroblasts [28
]. The pathologic impact of tubular EMT on renal fibrogenesis is two folds: it leads to tubular atrophy due to a decreased epithelial cell mass, and it increases the matrix-producing effector cells. Emerging evidence suggests that EMT is a crucial event in the evolution of renal interstitial fibrosis; accordingly, blockade of EMT process via various strategies ameliorates fibrotic lesions in vivo [26
]. We have recently found that active vitamin D directly block tubular EMT induced by TGF-β1 in cultured tubular epithelial cells, as demonstrated by restoring E-cadherin expression and suppressing α-SMA and fibronectin expression. Therefore, active vitamin D can target a key cellular event in renal interstitial fibrogenesis.
Although tubula r EMT is very complex, the entire EMT course at cellular level is consisted of four key steps, in which loss of epithelial cell-cell adhesion property, as manifested by suppression of E-cadherin, is an early, initial event [28
]. Our recent studies demonstrate that active vitamin D preserves E-cadherin expression by suppressing Snail and Id expression (). In normal physiologic conditions, E-proteins, a family of basic helix-loop-helix (bHLH) transcription factors, form a homo- or heterodimers and bind to the E-boxes in the E-cadherin promoter and trans
-activate its gene transcription. However, in the fibrotic kidney or upon stimulation with TGF-β1 in vitro, tubular epithelial cells over-express Snail and Id proteins. Snail, a zinc-finger transcription factor that plays a critical role in EMT in a wide range of carcinomas [32
], possesses DNA-binding capacity and is able to specifically bind to the core E-box, thereby displacing E-proteins and sequestering their ability to activate E-cadherin gene expression (). Id, a family of transcriptional inhibitors, represents a truncated form of bHLH proteins. Because of lacking the basic DNA-binding region, Id is unable to bind to DNA but retains its ability to heterodimerize with other E-proteins, and thus functions as a transcriptional antagonist in a dominant-negative fashion [35
]. Increased Id, therefore, physically binds to E-proteins and prevents their interacting with E-box, thereby inhibiting the trans
-activating capacity of E-proteins (). The ability of active vitamin D to inhibit both Snail and Id in vivo and in vitro highlights that it can restore E-cadherin and preserve the integrity of tubular epithelium in CKD.
Figure 2 Active vitamin D preserves renal epithelial cell phenotypes by suppressing Snail and Id expression. In normal physiologic conditions, E-proteins, a family of bHLH transcription factors, bind to the E-boxes and trans-activate E-cadherin and vitamin D receptor (more ...)
VDR gene harbors E-boxes and is therefore suppressed by Snail and Id in diseased kidney [36
]. Through the similar mechanisms as described in , active vitamin D effectively restores VDR expression in CKD. Studies also indicate that VDR could physically form complexes with β-catenin [37
], a major signaling mediator that integrates the signals from diverse pathways and plays a critical role in EMT. β-catenin is known to form a complex with T cell transcription factor (TCF)-4; and together they trans
-activate the transcription of their target genes. Ligand-activated VDR competes with TCF-4 for β-catenin binding, and represses β-catenin/TCF-4-mediated gene transcription. In this regard, down-regulation of VDR in CKD, in essence, removes the negative control mechanism for β-catenin signaling, and effectively promotes the expression of the EMT-related genes. Active vitamin D, through induction of VDR, restates the mechanism that confines β-catenin signaling, thereby preserving the tubular epithelial phenotypes of renal parenchyma.
At present, although the data regarding the role of active vitamin D in renal tubules are limited, available results have suggested a fundamental role for active vitamin D in the maintenance of the structural and functional integrity of tubular epithelium. As the pathologic significance of tubular EMT in renal fibrosis is increasingly recognized, so does the role of active vitamin D in renal protection.