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Abstract: SA-PO267

Pharmacological Inhibition of Lysine-Specific Histone Demethylase 1 Protects Against AKI

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Jiao, Baihai, UConn Health, Farmington, Connecticut, United States
  • Du, Hao, UConn Health, Farmington, Connecticut, United States
  • Tran, Melanie, UConn Health, Farmington, Connecticut, United States
  • Song, Bo, UConn Health, Farmington, Connecticut, United States
  • Wang, Yanlin, UConn Health, Farmington, Connecticut, United States
Background

Acute kidney injury (AKI) is a common clinical condition associated with increased mortality and morbidity. Current therapeutic options for this serious disorder are often limited and ineffective. Therefore, new therapeutic strategies are urgently needed to prevent or treat AKI. Macrophages play a critical role in the pathogenesis of cisplatin-induced AKI. However, the molecular mechanisms underlying macrophage activation in AKI are not fully elucidated. In this study, we investigated the role of lysine-specific histone demethylase 1 (LSD1) in the regulation of macrophage activation in the development of cisplatin-induced AKI.

Methods

To examine the role of LSD1 in cisplatin-induced AKI in vivo, wild-type C57BL6/J mice were administered intraperitoneally with a single dose of 20 mg/kg cisplatin to induce AKI and treated with GSK-LSD1, a selective LSD1 inhibitor, at 1 mg/kg or vehicle daily by intraperitoneal injection for 3 days. Cultured bone marrow-derived macrophages were used to examine the role and mechanisms of LSD1 in the regulation of macrophage activation in vitro.

Results

The expression of LSD1 was increased in macrophages in the kidney following cisplatin-induced AKI. Pharmacological inhibition of LSD1 with GSK-LSD1 protected the kidney from cisplatin-induced AKI and preserved kidney function in vivo. Furthermore, pharmacological inhibition of LSD1 with GSK-LSD1 suppressed macrophage activation, attenuated the NLRP3 expression, and inhibited inflammasome activation, resulting in reduced cleaved caspase 1 and IL-1β levels in the kidneys of cisplatin-induced AKI. In bone marrow-derived macrophages, pharmacological inhibition of LSD1 with GSK-LSD1 abolished macrophage activation and suppressed proinflammatory cytokine production. Moreover, GSK-LSD1 blocks NLRP3 expression and inflammasome activation in bone marrow-derived macrophages.

Conclusion

Our study identifies LSD1 as a critical regulator of NLRP3 expression and inflammasome activation in macrophages, leading to proinflammatory molecule production and development of cisplatin-induced AKI. Therefore, targeting LSD1 may represent a novel therapeutic strategy for AKI.

Funding

  • NIDDK Support