#2671 Renal tubular epithelial FFAR4 improves cellular senescence to alleviate interstitial fibrosis in CKD

Abstract

Abstract Background and Aims Chronic kidney disease (CKD) is defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 or pathological albuminuria, which is known as one of the major contributors to worldwide mortality. Although there have been substantial advances in understanding CKD mechanisms, at present, there are no effective therapies to treat it. We had formerly found that TUG891, a free fatty acid receptor 4 (FFAR4) (a member of the G protein-coupled receptor (GPCR) family) agonist, alleviated tubular damage as well as interstitial fibrosis in mice with CKD. Nevertheless, the multifunctional effects of FFAR4 in the kidney have not been well described. Method In the current research, the FFAR4 expression was abnormally reduced in tubular epithelial cells (TECs) of unilateral ureteral obstruction (UUO) and adenine-induced CKD mice. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function, pathological damage and interstitial fibrosis, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in UUO and adenine-induced CKD mice. Results Notably, FFAR4, as a key determinant, was firstly explored to regulate the cellular senescence in TECs and CKD 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 FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in UUO and adenine-induced CKD mice. Conclusion These results underline the primordial role of renal tubular FFAR4 in the cellular senescence through AMPK/SirT3 signaling and define FFAR4 as a target for underlying drugs against CKD.