Inhibition of Jumonji C domain histone demethylases by JIB-04 exacerbates ischemia-reperfusion injury and maladaptive repair in females lacking ovarian hormones.

The female sex confers protection against ischemia-reperfusion injury (IRI) in the kidneys. Jumonji-domain-containing histone demethylases (JmjCs), a family of enzymes involved in epigenetic modulation, have been implicated in hypoxia and renal disease. Although epigenetic changes occur during hormone signaling, the role of JmjCs in the epigenetic regulation of sex-associated ischemic tolerance remains unclear. In this study, a unilateral IRI model was employed in male (intact and gonadectomized) and female (estrus, diestrus, and ovariectomized) C57BL/6 mice subjected to 30 min of ischemia or sham surgery, followed by 6 h, 24 h, or 20 days of reperfusion, with or without pretreatment using JIB-04 (100 mg/kg), a broad-spectrum inhibitor of JmjC demethylase activity. Renal function markers, expression of selected JmjC family members, and kidney remodeling after IRI were assessed using colorimetric analysis, RT-qPCR, histology, immunohistochemistry, and enzyme-linked immunosorbent assays. Sex, gonadectomy, and the estrous cycle modulated IRI-induced renal damage and the expression of selected JmjC family members. Pharmacological inhibition of JmjC activity with JIB-04 increased renal injury in females, and exacerbated kidney fibrosis in ovariectomized females. These effects were associated with increased expression of transforming growth factor-beta 1 and thioredoxin domain-containing 5. The findings indicate that pharmacological inhibition of JmjC demethylase activity influences sex- and hormone-dependent responses to renal IRI and suggest that ovarian hormones may influence the renal response to pharmacological inhibition of JmjC demethylase activity during IRI.