The hypoxia-inducible factor-α prolyl hydroxylase inhibitor FG4592 ameliorates renal fibrosis by inducing the H3K9 demethylase JMJD1A

Hypoxia-inducible factors 1α and 2α (HIF-1α/2α) transcription factors are the major regulators of the cellular response to hypoxia and also play a key role in renal fibrosis associated with acute and chronic kidney disease. Jumonji domain-containing 1a (JMJD1A), a histone H3 lysine 9 (H3K9) demethylase, is reported to be an important target gene of HIF-α. However, whether JMJD1A and H3K9 methylation status play a role in renal fibrosis is unclear. Here, we investigated the involvement of HIF-α, JMJD1A, and monomethylated/dimethylated H3K9 (H3K9me1/H3K9me2) levels in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Intraperitoneal administration of FG4592, an inhibitor of HIF-α prolyl hydroxylase (PH), which controls HIF-α protein stability, significantly attenuated renal fibrosis on days 3 and 7 following UUO. FG4592 concomitantly increased JMJD1A expression, decreased methylated H3K9me1/me2 levels, reduced pro-fibrotic gene expression, and increased erythropoietin expression in renal tissues of UUO mice. The beneficial effects of FG4592 on renal fibrosis were inhibited by administration of JMJD1A-specific siRNA to mice immediately following UUO. Incubation of NRK-49F normal rat kidney cells with transforming growth factor-β1 (TGF-β1) in vitro resulted in upregulated expression of α-smooth muscle actin and H3K9me1/me2, and these effects were inhibited by co-treatment with FG4592. In contrast, FG4592 treatment further enhanced the TGF-β1-stimulated upregulation of JMJD1A but had no effect on TGF-β1-stimulated expression of the H3K9 methyltransferase euchromatic histone-lysine N-methyltransferase 2. Collectively, these findings establish a crucial role for the HIF-α1/2-JMJD1A-H3K9me1/me2 regulatory axis in the therapeutic effect of FG4592 in renal fibrosis.

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