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Effects of long-term tubular HIF-2メ overexpression on progressive renal fibrosis in a chronic kidney disease model
Dal-Ah Kim1,# (Research professor), Mi-Ran Lee2,# (Professor), Hyung Jung Oh3 (Professor), Myoung Kim4 ( Professor), Kyoung Hye Kong 1,* (Research professor)
1Ewha Medical Research Center, Ewha Womans University,
2Department of biomedical Laboratory Science, Jungwon University,
3Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital,
4Department of Urology, Ewha Womans University Seoul Hospital
Renal fibrosis is the final manifestation of chronic kidney disease (CKD) regardless of etiology. Hypoxia-inducible factor-2 alpha (HIF-2メ) is an important regulator of chronic hypoxia, and the late-stage renal tubular HIF-2メ activation exerts protective effects against renal fibrosis. However, its specific role in progressive renal fibrosis remains unclear. In this study, we investigated the effects of the long-term tubular activation of HIF-2メ on renal function and fibrosis, using in vivo and in vitro models of renal fibrosis.
Progressive renal fibrosis was induced in renal tubular epithelial cells (TECs) of tetracycline-controlled HIF-2メ transgenic (Tg) mice and wild-type (WT) controls through a 6-week adenine diet. Tg mice were maintained on doxycycline (DOX) for the diet period to induce Tg HIF-2メ expression. Primary TECs isolated from Tg mice were treated with DOX (5 ug/ml), transforming growth factor-モ1 (TGF-モ1) (10 ng/ml), and a combination of both for 24, 48, and 72 hr. Blood was collected to analyze creatinine (Cr) and blood urea nitrogen (BUN) levels. Pathological changes in kidney tissues were observed using hematoxylin and eosin, Masson’s trichrome, and Sirius Red staining. Meanwhile, the expression of fibronectin, E-cadherin, メ-smooth muscle actin (メ-SMA), and phosphorylation of p38 mitogen-activated protein kinase (MAPK) was observed using western blotting.
Our data showed that serum Cr and BUN levels were significantly lower in Tg mice than in WT mice following the adenine diet. Moreover, the protein levels of fibronectin and E-cadherin and the phosphorylation of p38 MAPK were markedly reduced in the kidneys of adenine-fed Tg mice. These results were accompanied by attenuated fibrosis in Tg mice following adenine administration. Consistent with these findings, HIF-2メ overexpression significantly decreased the expression of fibronectin in TECs, whereas an increase in メ-SMA protein levels was observed after TGF-モ1 stimulation for 72 hr.
Taken together, these results indicate that long-term HIF-2メ activation in CKD may inhibit the progression of renal fibrosis and improve renal function, suggesting that long-term renal HIF-2メ activation may be used as a novel therapeutic strategy for the treatment of CKD.
Abstract, Accepted Manuscript(in press) [Submitted on September 16, 2022, Accepted on November 19, 2022]
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