Role of hypoxia-inducible factor-1 in the development of renal fibrosis in mouse obstructed kidney: Special references to HIF-1 dependent gene expression of profibrogenic molecules

Abstract

The aim of the study is to clarify the role of hypoxia-inducible factor-1 (HIF-1) in the development of renal fibrosis in mouse obstructive nephropathy. We used mice with floxed HIF-1α alleles and tamoxifen-inducible Cre/ERT2 recombinase under ubiquitin C promoter to induce global HIF-1α deletion. Following tamoxifen administration, mice were subjected to unilateral ureteral obstruction (UUO). At 3, 7 and 14 days after UUO, renal gene expression profiles and interstitial fibrosis were assessed. HIF-1 dependent up-regulation of prolyl hydroxylase 3 and glucose transporter-1 was observed in the obstructed kidney at 3 and 7 days but not at 14 days after UUO. Various factors promoting fibrosis were up-regulated during the development of fibrosis. HIF-1 dependent gene expression of profibrotic molecules, plasminogen activator inhibitor 1, connective tissue growth factor, lysyl oxidase like 2 and transglutaminase 2 was observed in the obstructed kidney but such HIF-1 dependency was limited to the early onset of renal fibrosis. Global HIF-1 deletion tended to attenuate interstitial collagen I deposition at 3 days but had no effects thereafter. It is suggested that HIF-1 dependent profibrogenic mechanisms are operating at the early onset of renal fibrosis but its contribution declines with the progression in mouse UUO model.