Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy

Abstract

Deficiency in vitamin D and its active metabolites is a pathologic feature of chronic kidney diseases. Despite that tubular epithelial cells are the major sites of active vitamin D synthesis, little is known about the role of vitamin D in maintaining the structural and functional integrity of tubular epithelium. This study investigated the effects of paricalcitol (19-nor-1,25-hydroxy-vitamin D2), a synthetic vitamin D analogue, on obstructive nephropathy, a model that is characterized by predominant tubulointerstitial lesions. Compared with vehicle controls, paricalcitol significantly attenuated renal interstitial fibrosis in mouse kidney after ureteral obstruction, as demonstrated by a reduced interstitial volume, decreased collagen deposition, and repressed mRNA expression of fibronectin and type I and type III collagens. Paricalcitol largely preserved E-cadherin and reduced α-smooth muscle actin expression in vivo. In addition, paricalcitol suppressed renal TGF-β1 and its type I receptor expression, restored vitamin D receptor abundance, and inhibited cell proliferation and apoptosis after obstructive injury. In vitro, paricalcitol abolished TGF-β1-mediated E-cadherin suppression and α-smooth muscle actin and fibronectin induction in tubular epithelial cells, underscoring its ability to block directly the epithelial to mesenchymal transition (EMT). It is interesting that paricalcitol almost completely suppressed renal induction of Snail, a critical transcription factor that is implicated in EMT programming. Furthermore, paricalcitol inhibited the TGF-β1-mediated Snail induction in vitro, and ectopic expression of Snail repressed E-cadherin promoter activity and downregulated E-cadherin expression in tubular epithelial cells. These studies suggest that paricalcitol is able to ameliorate renal interstitial fibrosis in obstructive nephropathy, possibly by preserving tubular epithelial integrity through suppression of EMT. Copyright © 2006 by the American Society of Nephrology.