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MicroRNAs (miRNAs) play a critical role in regulating the response of animals exposed to heavy metal stress. As a globally dispersed heavy metal in aquatic ecosystems, cadmium (Cd) is highly toxic to many aquatic species. However, little is known about the miRNA response to Cd stress in fish. To investigate the regulatory effect of miRNAs in response to Cd, common carp (Cyprinus carpio) were exposed to Cd2+-containing water (0.005 mg/L, 0.05 mg/L, 0.5 mg/L) for 30 days. After exposure, Cd2+ contents were significantly higher in the kidneys of C. carpio compared to other tissues, when exposed to 0.5 mg/L Cd2+. Hematoxylin and eosin staining images revealed that elevated Cd induced inflammatory damage in the kidneys of C.carpio. Further, miRNA sequencing revealed nine differentially expressed miRNAs (miR-217, miR-205 and seven novel miRNAs) in the kidneys, between 0.5 mg/L Cd2+ exposure and control groups. Potential target mRNAs of miRNAs suggest that miR-217 is involved in immunotoxicity. miR-217 agomir was intraperitoneally administered to C. carpio and RT-PCR revealed that the expression of IL-8 and SIRT1 decreased, while TLR-4, TRAF6, NF-kB, TNF-α, IL-1β, and TGF-β increased in the kidneys of C.carpio. Additionally, the expression of SIRT1 decreased, while the expression of other mRNAs increased in kidneys of C. carpio exposed to Cd. According to mRNAs expression in the agomir and Cd treatment, miRNAs inhibit the expressions of target mRNAs. These results demonstrate that miR-217 via SIRT1 plays a regulatory role in the immunotoxicity of Cd to C. carpio. [Display omitted] • miRNA sequencing and RT-PCR revealed 8 differentially expressed miRNAs in the kidneys of Cyprinus carpio after Cd exposure. • Overexpression of miR-217 affects the expressions of immune genes in the kidneys of C. carpio. • miR-217 via SIRT1, regulates Cd-induced immune responses in the C. carpio. [ABSTRACT FROM AUTHOR]