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Abstract: SA-PO093

Inhibition of KDM5 Attenuates Renal Fibrosis After Ischemic Kidney Injury

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Jo, Wonji, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Park, Junkyu, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Koh, Eun Sil, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Chung, Sungjin, The Catholic University of Korea, Seoul, Korea (the Republic of)
Background

The histone lysine demethylases 5 (KDM5) are members of the family of Jumonji C domain-containing histone demethylases and catalyze the removal of di- and tri-methyl moieties from the fourth lysine of histone 3 (H3K4me2/3). It has been reported that the KDM5 family mediates a range of physiological and pathological events including cell differentiation, motility, senescence and epithelial-mesenchymal transition (EMT) via activating or repressing transcription in demethylase-dependent or independent manners in both homeostasis and disease. This study investigated the potential role of KDM5 in the development and progression of renal fibrosis in acute kidney injury (AKI) or chronic kidney disease (CKD).

Methods

We evaluated therapeutic effects of KDM5 inhibition in AKI model of unilateral nephrectomy plus contralateral ischemia-reperfusion (IR) injury, AKI to CKD model of unilateral IR injury plus removal of contralateral uninjured kidney after 8 days of IR injury, and CKD model of unilateral ureteral obstruction (UUO) in mice.

Results

KDM5 C70 inhibitor prevented the increase of blood urea nitrogen and positive areas of trichrome, Sirius red, F4/80 and α-smooth muscle actin in injured kidneys 7 days after IR injury. Significant reductions in renal mRNA levels of pro-inflammatory cytokine/chemokine, EMT and pro-fibrotic markers (IL-1β, IL-6, TNF-α, CCL2, CCL3, GM-CSF, MMP9, fibronectin, vimentin, TGF-β1, COL4A1) were also observed with attenuated mRNA levels of KDM5a-c. In addition, renal protein levels of antioxidants such as catalase, SOD1 and SOD2 were increased in injured kidneys of KDM5 inhibitor-treated mice. However, parameters of renal fibrosis and inflammation were similar between mice without and with KDM5 inhibitor in both AKI-CKD and CKD models.

Conclusion

These data demonstrate that inhibition of KDM5 could prevent renal inflammation and fibrosis after acute and severe IR injury. The activation of KDM5 might be an early step in the development of renal fibrosis after AKI insult.

Funding

  • Government Support – Non-U.S.