Tubular Omega‐3 Fatty Acid Receptor <scp>FFAR4</scp> Deficiency Aggravated Renal Aging and Chronic Kidney Disease

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.