Empagliflozin Attenuates Hyperuricemia by Upregulation of ABCG2 via AMPK/AKT/CREB Signaling Pathway

Background: Hyperuricemia (HUA) is a metabolic disease characterized by elevated serum uric acid (SUA). Empagliflozin, a kind of sodium-glucose cotransporter 2 inhibitors, has recently emerged as a new antidiabetic agent by facilitating glucose excretion in urine. Moreover, there was evidence of SUA reduction following treatment with empagliflozin in addition to glycaemic control, while the molecular mechanisms remain unknown. Methods: The model of type 2 diabetes (T2DM) with HUA was established by combination of peritoneal injection of potassium oxonate and intragastric administration of hypoxanthine in KK-Ay mice. A series of method such as RT-PCR, western blot, immunochemistry, immunofluorescence were conducted to explore the mechanism. Findings: Our results showed that empagliflozin significantly ameliorated the levels of SUA and blood glucose in T2DM mice with HUA. Furthermore, in both kidney and ileum, empagliflozin obviously promoted protein expression of UA transporter ABCG2, p-AMPK, p-Akt and p-CREB. The same trend was observed in human tubular epithelial (HK-2) cells. Additionally, through application of an AMPK inhibitor (compound C), it was further confirmed empagliflozin exerted its anti-hyperuricemic effects in an AMPK dependent manner. Meanwhile, with the help of ChIP assay and luciferase reporter gene assay, we found that CREB further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Interpretation: Our study demonstrated for the first time that empagliflozin treatment played an essential role in attenuating HUA by upregulation of ABCG2 via AMPK/Akt/CREB signaling pathway. Funding Statement: This work was supported by National Natural Science Foundation of China (81470187), a grant from the Natural Science Foundation of Tianjin (15ZXHLSY00460, 18JCYBJC26100 and 18JCZDJC35500), a grant from National Natural Science Foundation of China (31800722), a grant from Tianjin Municipal Education Commission (2017KJ210). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was approved by the ethical committee of Tianjin Medical University, and all procedures involving mice were conducted according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health as well as the guidelines of the Animal Welfare Act.