Inhibition of HIF-la activity is a novel strategy for the treatment of tubulointerstitial fibrosis

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Chronic hypoxia is a main contributor to the progression of tubulointerstitial fibrosis. In this study, we investigated the extent to which hypoxia-inducible factor 1α (HIF-1α) mediates epithelial-mesenchymal-transition (EMT) in vivo and in vitro using a mouse model in which renal proximal epithelial HIF-1α expression was selectively deleted and assessed the role of HIF-1α in EMT-mediated renal fibrosis. In addition, we developed a method with which to detect EMT in vitro, using Cre-recombinase activated β-galactosidase (LacZ) to identify and track primary tubular epithelial cells (TECs). To determine whether HIF-la is involved in the development of tubulointerstitial fibrosis in vivo, renal fibrosis was induced by unilateral urethral obstruction (UUO) in HIF-la-mutant and wild-type mice. Kidneys were harvested for immunohistochemistry 8 days after UUO and stained for FSP1 (fibroblast-specific protein 1, a marker for EMT) using a modified ABC-peroxidase method. Numbers of FSP1+ cells w … More ere significantly lower in obstructed kidneys from HIF-1α-mutant than wild type mice. Moreover, after exposure to hypoxia (1% O_2), but not normoxia (20.9% O_2), for 5 days cultured TECs permanently marked with LacZ assumed a fibroblast-like morphology. And double staining for LacZ and FSP1 revealed that whereas 8.2% of TECs underwent EMT (LacZ+/FSP1+) under normoxic conditions, 28.3% underwent EMT under hypoxic conditions. We also determined that blockade of HIF-1α activity can be a novel approach for the treatment of tubulointerstitial fibrosis through the inhibition of epithelial-mesenchymal-transition (EMT) in vitro and in vivo, using YC-1(3-(5'-hydroxymethy1-2'-fury1)-1-benzyl indazole) as an anti-HIF-1α agent.Taken together, our results suggest that, through activation of HIF-1, hypoxia plays a key role in the induction of EMT and in EMT-mediated renal fibrosis in vitro and in vivo and anti-HIF-1α agents may be utilized for the treatment of tubulointerstitial fibrosis through the inhibition of EMT. Less