title: 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 D(2)), 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 alpha-smooth muscle actin expression in vivo. In addition, paricalcitol suppressed renal TGF-beta1 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-beta1-mediated E-cadherin suppression and alpha-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-beta1-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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015820:Cadherins / Q000187:drug effects; D002118:Calcium / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D004872:Ergocalciferols / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis / Q000188:drug therapy; D007676:Kidney Failure, Chronic / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010281:Parathyroid Hormone / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D014808:Vitamin D Deficiency / Q000150:complications*; D014815:Vitamins / Q000494:pharmacology*; D016335:Zinc Fingers
chemical_list: D000199:Actins; D015820:Cadherins; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018125:Receptors, Transforming Growth Factor beta; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D014815:Vitamins; C084656:paricalcitol; D002118:Calcium