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Kidney Week

Abstract: TH-PO957

Effect of Long-Term Tubular Overexpression of Hypoxia-Inducible Factor-2a on the Progressive Renal Fibrosis in a CKD Model

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Kong, Kyoung Hye, Ewha Womans University, Seoul, Korea (the Republic of)
  • Oh, Hyung Jung, Ewha Womans University, Seoul, Korea (the Republic of)
  • Ryu, Dong-Ryeol, Ewha Womans University, Seoul, Korea (the Republic of)
Background

Although hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia, and the effect of selective tubular activation of HIF-2α on renal fibrosis was demonstrated recently, there is no study for the effect of long-term tubular activation of HIF-2α on the progressive renal fibrosis.

Methods

We are mainly performed using PAX8-rtTA/tetO-Cre/HIF2dPA-HA transgenic mice(Tg). For the induction of renal fibrosis and CKD, the mice were fed a 0.2% adenine-containing diet for 2, 4, and 6 weeks with doxycycline (DOX, 2mg/ml) administration at day 0. Moreover, isolated primary renal tubular epithelial cells (TECs) from Tg mice were divided into one of four groups: the control, DOX (5ug/ml), TGF-β1(10ng/ml), and DOX+TGF-β1 groups (for 24, 48 and 72 h), in vitro. For renal function, Cr and BUN were measured, and real-time PCR, western blotting and immunohistochemical staining were performed.

Results

Serum Cr and BUN levels were significantly higher in WT and Tg CKD mice compared with the control mice at 2, 4 and 6 weeks. However, those levels of only 6-week HIF-2α activated CKD mice were significantly decreased compared to those in 6-week WT CKD model. The WB (fibronectin, E-cad/α-SMA, type I collagen) and IHC also showed the increased renal fibrosis in WT CKD mice at 2, 4 and 6 weeks compared with control mice. However, in only 6-week Tg CKD mice, the increased fibrosis was significantly attenuated compared to that in the same week WT CKD mice. In vitro, the increased fibronectin and type I collagen protein expressions after TGF-β1 stimulation were significantly decreased in the 72 h HIF-2α continuous activation except for 24 and 48 h groups.

Conclusion

These findings showed that long-term HIF-2α activation in CKD might inhibit the progression of renal fibrosis and improve renal function, which suggests that long-term renal HIF-2α activation could represent a new therapeutic way in CKD.

Funding

  • Other NIH Support