Letian Yang, Lei Tang, Jian Li, Dekai Liu, Chunchun Hu, Fan Guo, Lin Lin, Rongshuang Huang, Ping Fu, Liang Ma
Aging leads to renal function decline and increases the risk of chronic kidney disease (CKD). Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids for humans, exerting their functions via free fatty acid receptor 4 (FFAR4). Clinical studies indicate that omega-3 PUFAs supplementation shows benefits for the elderly population and CKD patients, but these results remain controversial. Herein, we found that omega-3 PUFAs alleviated renal fibrosis and tubular senescence in aged mice, adenine diet-induced CKD mice, and unilateral ureteral obstruction (UUO) mice. Meanwhile, omega-3 fatty acid receptor FFAR4 expression in tubular epithelial cells (TECs) were down-regulated in the old population and CKD patients, positively correlated with renal dysfunction. Systemic or TEC-specific knockout of FFAR4 aggravated renal aging and CKD in mice. Mechanically, FFAR4 agonism increases the production of endogenous PPARγ activator 15-deoxy-∆12,14-Prostaglandin J2 (15d-PGJ2), and improves PPARγ-dependent tubular epithelial cell senescence, which was indicated by anti-aging marker Klotho expression, senescence-associated β-galactosidase (SA-β-gal) activity, and profibrotic factor TGF-β1 secretion. The study demonstrated a novel role of FFAR4 from senescent TECs on fibroblast activation via paracrine effects and highlighted the therapeutic effects of omega-3 PUFAs with their receptor FFAR4 as an attractive drug target against renal aging and CKD.