Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.
Bibliographical noteFunding Information:
We are deeply grateful to William G. Kaelin at the Dana-Farber Institute, Harvard Cancer Center for kindly providing HIF transgenic mice, and also thank Andras Nagy and Marina Gertsentein of the Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada for providing TeT-O-Cre transgenic mice. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2009837), NRF grant funded by the Korean Government (MEST) (NRF-2015R1A2A2A01002308), and Basic Science Research Program through the NRF funded by the Ministry of Science, ICT & Future Planning (2010-0027945).
All Science Journal Classification (ASJC) codes