Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis

Abstract

Vitamin D, especially its most active metabolite 1,25-dihydroxyvitamin D(3) or calcitriol, is essential in regulating a wide variety of biologic processes, such as calcium homeostasis, immune modulation, cell proliferation and differentiation. Clinical studies show that the circulating level of calcitriol is substantially reduced in patients with chronic renal insufficiency. Administration of active Vitamin D results in significant amelioration of renal dysfunction and fibrotic lesions in various experimental models of chronic kidney diseases. Active Vitamin D elicits its renal protective activity through multiple mechanisms, such as inhibiting renal inflammation, regulating renin-angiotensin system and blocking mesangial cell activation. Recent studies indicate that calcitriol induces anti-fibrotic hepatocyte growth factor expression, which in turn blocks the myofibroblastic activation and matrix production in interstitial fibroblasts. Furthermore, in vivo and in vitro studies demonstrate that active Vitamin D effectively blocks tubular epithelial to mesenchymal transition (EMT), a phenotypic conversion process that plays a central role in the evolution of renal interstitial fibrosis. Together, it is becoming increasingly clear that a high level of active Vitamin D may be obligatory in the maintenance of normal kidney structure and function. Thus, supplementation of active Vitamin D could be a rational strategy for the therapeutics of chronic kidney diseases.

Figure 1

Active vitamin D may inhibit the activation of renal fibrogenic cells by inducing anti-fibrotic HGF expression. (A, B) Active vitamin D induces HGF mRNA expression and protein secretion in renal interstitial fibroblasts (NRK-49F), as shown by RT-PCR (A) and Western blot analyses (B). (C) Diagram shows the potential pathways leading to vitamin D inhibition of renal fibrosis. Ligand-bound VDR trans-activate HGF gene expression (1). Increased HGF upreguates Smad co-repressor TGIF expression and inhibits mesangial cell activation (2). HGF blocks the nuclear translocation of the activated-Smads in renal interstitial fibroblasts, thereby preventing myofibroblast activation (3). In tubular epithelial cells, HGF induces SnoN expression, thereby inhibiting TGF-β/Smad-mediated tubular EMT (4). TGF-β1, via its Smad signaling, promotes tubular EMT and myofibroblastic activation from glomerular mesangial cells and interstitial fibroblasts, respectively (5). Panels A and B of this figure are reproduced from the published work with permission [21].

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 genes (1). In the fibrotic kidney, an increased Snail and Id proteins repress E-box-mediated gene expression through distinctive mechanisms. Snail displaces E-proteins from binding to the E-boxes via its DNA-binding capacity (2), whereas Id sequesters the gene activating activity of E-proteins through physically interacting with them (3).