#6747 ACTIVATION OF GPR120 IMPROVES THE SENESCENCE OF TUBULAR EPITHELIAL CELLS IN SEPTIC ACUTE KIDNEY INJURY

Abstract

Abstract Background and Aims Acute kidney injury (AKI) is a serious clinical complication that has high morbidity and mortality. Although there have been substantial advances in understanding AKI mechanisms, at present, there are no effective therapies to treat or prevent it. Method We had formerly found that TUG891, a GPR120 (a member of the G protein-coupled receptor (GPCR) family) agonist, alleviated tubular damage as well as renal dysfunction in mice with AKI. Nevertheless, the multifunctional effects of FFAR4 in the kidney have not been well described. Results In the current research, the GPR120 expression was abnormally reduced in tubular epithelial cells (TECs) of cecal ligation/perforation induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of GPR120 aggravated renal function and pathological damage, whereas GPR120 activation by TUG-891 alleviated the severity of disease in AKI mice induced with cisplatin. Notably, GPR120, as a key determinant, was firstly explored to regulate the cellular senescence in TECs and AKI mice injured kidneys, as represented through the activity of senescence associated β-galactosidase (SA-β-gal), marker protein p21, p53, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where GPR120 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and tubular epithelial cells. Conclusion These results underline the primordial role of renal tubular GPR120 in the cellular senescence through AMPK/SirT3 signaling and define GPR120 as a target for underlying drugs against septic AKI.