The
transcription factors hypoxia-inducible factor-1α and -2α (HIF-1α/2α) 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-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, which controls HIF-α 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-β1 (TGF-β1) in vitro resulted in upregulated expression of α-smooth muscle actin and H3K9me1/me2, and these effects were inhibited by cotreatment 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.NEW & NOTEWORTHY Using a mouse model of renal
fibrosis and transforming growth factor-β1-stimulated rat cell lines, we show that treatment with
FG4592, an inhibitor of
hypoxia-inducible factor-1α and -2α (HIF-1α/2α)
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-1α/2α-JMJD1A-H3K9 regulatory axis in suppressing renal
fibrosis.