Inhibition of Histone Lysine Demethylases 5 Attenuates AKI but Does Not Impact Acute Kidney Disease or CKD

Background: Histone lysine demethylases 5 (KDM5) are part of the Jumonji C domain-containing family of histone demethylases, which catalyze the removal of di- and tri-methyl groups from the fourth lysine of histone 3 (H3K4me2/3). The KDM5 family is implicated in various physiological and pathological processes, including cell differentiation, motility, senescence, and epithelial-mesenchymal transition (EMT), through both demethylase-dependent and independent mechanisms in homeostasis and disease. This study investigated the role of KDM5 in renal fibrosis development and progression in acute kidney injury (AKI), chronic kidney disease (CKD), and the transition from AKI to CKD (acute kidney disease, AKD). Methods: The therapeutic effects of KDM5 inhibition were evaluated in three mouse models: AKI induced by unilateral nephrectomy plus contralateral ischemia-reperfusion (IR) injury, AKD induced by unilateral IR injury followed by removal of the contralateral uninjured kidney 8 days post-IR injury, and CKD induced by unilateral ureteral obstruction (UUO). Results: The KDM5 inhibitor C70 prevented increases in blood urea nitrogen and reduced areas stained by trichrome, Sirius red, F4/80, and α-smooth muscle actin in kidneys 7 days post-IR injury. Significant reductions in renal mRNA levels of pro-inflammatory cytokines/chemokines, EMT, and pro-fibrotic markers (IL-1β, IL-6, TNF-α, CCL2, CCL3, GM-CSF, MMP9, fibronectin, vimentin, TGF-β1, COL4A1) were observed, along with decreased mRNA levels of KDM5a-c. Additionally, renal protein levels of antioxidants such as catalase, SOD1, and SOD2 were increased in KDM5 inhibitor-treated mice. However, no significant differences in renal fibrosis and inflammation parameters were found between treated and untreated mice in both the AKD and CKD models. Conclusion: Inhibition of KDM5 can prevent renal inflammation and fibrosis following acute severe IR injury, suggesting that KDM5 activation may be an early step in the development of renal fibrosis after AKI. Funding: Government Support – Non-U.S.