GLP-1 Receptor Agonist Liraglutide and Its Metabolites Improve AKI by Inhibiting HMGB1 Acetylation in Renal Tubular Epithelial Cells

Background: Acute kidney injury (AKI) is a clinical complication characterized by a rapid decline in kidney function and the subsequent potential for chronic kidney fibrosis. It has been reported that the levels of HMGB1 are elevated in patients with AKI, which in turn activates pro-inflammatory signaling pathways, leading to severe organ damage. Liraglutide is a GLP-1R agonist used clinically as an antidiabetic drug. Our previous studies have shown that liraglutide exerts a direct renal protective effect which does not entirely depend on GLP-1R because that liraglutide is metabolized into smaller peptides in the body, which do not activate GLP-1R but have other biological effects. Based on this, we will further explore the mechanism by which liraglutide and its metabolites alleviate AKI in mice. Methods: Design and synthesize the metabolites of liraglutide, GLP-1(9-37) and GLP-1(28-37). An AKI model was established by intraperitoneally injecting 15 mg/kg of cisplatin into mice. HK-2 was cultured in a medium with cisplatin(12 μM) for 24 hours. Results: Liraglutide can, on one hand, activate GLP-1R to increase downstream cAMP levels, leading to the phosphorylation of AMPK, which in turn raises intracellular NAD+ levels and enhances the activity of NAD+-dependent SIRT1, thus inhibiting the acetylation of HMGB1; on the other hand, it can be metabolized into smaller peptides such as GLP-1(9-37) and GLP-1(28-37), which can directly enter cells and inhibit the acetylation of HMGB1 without GLP-1R, thereby inhibiting nucleocytoplasmic translocation and release of HMGB1, ultimately reducing AKI. Conclusion: This study elucidates the specific mechanism by which liraglutide improves AKI. At the same time, our research also found that, compared to liraglutide, the same dosage of GLP-1(9-37) and GLP-1(28-37) does not reduce the body weight of mice while protecting against AKI, providing new insights for the clinical treatment of AKI. Funding: Government Support – Non-U.S.