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

The transcription factors hypoxia-inducible factor-1 alpha and -2 alpha (HIF-1 alpha/2 alpha) are the major regulators of the cellular response to hypoxia and 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-alpha. However, whether JMJD1A and H3K9 methylation status play a role in renal fibrosis is unclear. Here, we investigated the involvement of HIF-alpha, 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-alpha prolyl hydroxylase, which controls HIF-alpha protein stability, significantly attenuated renal fibrosis on days 3 and 7 following UUO. FG4592 concomitantly increased JMJD1A expression, decreased H3K9me1/me2 levels, reduced profibrotic gene expression, and increased erythropoietin expression in renal tissues of UUO mice. The beneficial effects of FG4592 on renal fibrosis were inhibited by the administration of JMJD1A-specific siRNA to mice immediately following UUO. Incubation of normal rat kidney-49F and/or -52E cells with transforming growth factor-beta 1 (TGF-beta 1) in vitro resulted in upregulated expression of a-smooth muscle actin and H3K9me1/me2, and these effects were inhibited by cotreatment with FG4592. In contrast, FG4592 treatment further enhanced the TGF-beta 1-stimulated upregulation of JMJD1A but had no effect on TGF-beta 1-stimulated expression of the H3K9 methyltransferase euchromatic histone-lysine N-methyltransferase 2. Collectively, these findings establish a crucial role for the HIF-alpha 1/2-JMJD1A-H3K9me1/me2 regulatory axis in the therapeutic effect of FG4592 in renal fibrosis. NEW & NOTEWORTHY Using a mouse model of renal fibrosis and transforming growth factor-beta 1-stimulated rat cell lines, we show that treatment with FG4592, an inhibitor of hypoxia-inducible factor-1 alpha and -2 alpha (HIF-1 alpha/2 alpha) prolyl hydroxylase decreases renal fibrosis and concomitantly reduces methylated lysine 9 of histone H3 (H3K9) levels via upregulation of Jumonji domain-containing 1a (JMJD1A). The results identify a novel role for the HIF-1 alpha/2 alpha-JMJD1A-H3K9 regulatory axis in suppressing renal fibrosis.