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Publication
Paricalcitol protects against TGF-ß1-induced fibrotic responses in hypoxia and
stabilises HIF-a in renal epithelia.
Authors
Nolan KA, Brennan EP, Scholz CC, Cullen C, Ryan A, Taylor CT, Godson C
Submitted By
Catherine Godson on 9/4/2014
Status
Published
Journal
Experimental cell research
Year
2014
Date Published
8/5/2014
Volume : Pages
330 : 371 - 381
PubMed Reference
25107382
Abstract
Epithelial injury and tubulointerstitial fibrosis (TIF) within a hypoxic
microenvironment are associated with progressive loss of renal function in
chronic kidney disease [CKD]. Transforming growth factor beta-1 (TGF-ß1) is an
important mediator of renal fibrosis. Growing evidence suggests that Vitamin D
[1,25-(OH)2D] and its analogues may have a renoprotective effect in CKD. Here we
examined the protective effect of the vitamin D analogue paricalcitol [PC;
19-nor-1a,3ß,25-trihydroxy-9,10-secoergosta-5(Z),7(E) 22(E)-triene] on the
responses of human renal epithelial cells to TGF-ß1. PC attenuated
TGF-ß1-induced Smad 2 phosphorylation and upregulation of the Notch ligand
Jagged-1, a-smooth muscle actin and thrombospondin-1 and prevented the
TGF-ß1-mediated loss of E-Cadherin. To mimic the hypoxic milieu of CKD we
cultured renal epithelial cells in hypoxia [1% O2] and observed similar
attenuation by PC of TGF-ß1-induced fibrotic responses. Furthermore, in cells
cultured in normoxia [21% O2], PC induced an accumulation of hypoxia-inducible
transcription factors (HIF) 1a and HIF-2a in a time and concentration [1µM-2µM]
dependent manner. Here, PC-induced HIF stabilisation was dependent on activation
of the PI-3Kinase pathway. This is the first study to demonstrate regulation of
the HIF pathway by PC which may have importance in the mechanism underlying
renoprotection by PC.
Investigators with authorship
Name
Institution
Catherine Godson
University College Dublin
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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