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Biochim Biophys Acta
2013[Jun]; 1833
(6
): 1454-62
PMID23466866
show ga
Transforming growth factor beta 1 (TGF-?1)-induced epithelial-mesenchymal
transition (EMT) in kidney epithelial cells plays a key role in renal
tubulointerstitial fibrosis in chronic kidney diseases. As hypoxia-inducible
factor (HIF)-1? is found to mediate TGF-?1-induced signaling pathway, we tested
the hypothesis that HIF-1? and its upstream regulator prolyl hydroxylase
domain-containing proteins (PHDs) are involved in TGF-?1-induced EMT using
cultured renal tubular cells. Our results showed that TGF-?1 stimulated EMT in
renal tubular cells as indicated by the significant decrease in epithelial marker
P-cadherin, and the increase in mesenchymal markers ?-smooth muscle actin (?-SMA)
and fibroblast-specific protein 1 (FSP-1). Meanwhile, we found that TGF-?1
time-dependently increased HIF-1? and that HIF-1? siRNA significantly inhibited
TGF-?1-induced EMT, suggesting that HIF-1? mediated TGF-?1 induced-EMT. Real-time
PCR showed that PHD1 and PHD2, rather than PHD3, could be detected, with PHD2 as
the predominant form of PHDs (PHD1:PHD2=0.21:1.0). Importantly, PHD2 mRNA and
protein, but not PHD1, were decreased by TGF-?1. Furthermore, over-expression of
PHD2 transgene almost fully prevented TGF-?1-induced HIF-1? accumulation and EMT
marker changes, indicating that PHD2 is involved in TGF-?1-induced EMT. Finally,
Smad2/3 inhibitor SB431542 prevented TGF-?1-induced PHD2 decrease, suggesting
that Smad2/3 may mediate TGF-?1-induced EMT through PHD2/HIF-1? pathway. It is
concluded that TGF-?1 decreased PHD2 expression via an Smad-dependent signaling
pathway, thereby leading to HIF-1? accumulation and then EMT in renal tubular
cells. The present study suggests that PHD2/HIF-1? is a novel signaling pathway
mediating the fibrogenic effect of TGF-?1, and may be a new therapeutic target in
chronic kidney diseases.
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