#3768 CDYL IS A THERAPEUTIC TARGET FOR ACUTE KIDNEY INJURY BY REGULATION PYROPTOSIS

Abstract

Abstract Background and Aims Pyroptosis as a necrosis type related to inflammation, is involved in various diseases, including acute kidney injury (AKI). Here, we report that Chromodomain Y-like (CDYL) is critical for pyroptosis regulation in AKI. Method Cisplatin-induced mouse model and cisplatin-induced TCMK-1 cell model of AKI were established, serum creatinine (Cr) and blood urea nitrogen (BUN) were measured to evaluate kidney function, and renal tissue lesions were observed by HE staining. The expression of gene/protein in relation to inflammation and pyroptosis were measured by qPCR and western blot. The CDYL was overexpression in mice by rapid injection of a volume of naked plasmid DNA solution (30 ug) through the tail vein 2 hours before intraperitoneal injection of cisplatin. Results The results indicate that CDYL was increased in cisplatin-induced and sepsis-induced AKI, and overexpression of CDYL in mice would significantly increase the expressions of NGAL, NLRP3, Caspase-1, GSDMD, IL-1β, MCP-1, TNFα and IL-6 (Fig. 1). RNA-seq shown that the genes were mainly enriched in fatty acid metabolic process when CDYL overexpression, and FABP4 was finally identified as the key downstream factor (Fig. 2). Overexpression of CDYL in cisplatin-induced AKI further aggravated renal injury compared with the model mice, as indicated by the increased inflammation and pyroptosis protein expression, and worse tissue architecture, while the knockout of FABP4 will attenuate the injury (Fig. 3). In addition, treatment with CDYL inhibitors could attenuate inflammation and pyroptosis in cisplatin-induced renal injury (Fig. 4) and cisplatin-stimulated TCMK-1 cells (Fig. 5). Conclusion CDYL played a role in inflammation and pyroptosis regulation in AKI. Inhibition of CDYL could suppress renal inflammatory response and pyroptosis, and improve kidney function via modulation of FABP4 expression. The results highlighted that CDYL might represent a potential therapeutic target against AKI.