Omega-3 polyunsaturated fatty acids alleviate renal fibrosis in chronic kidney disease by reducing macrophage activation and infiltration through the JAG1-NOTCH1/2 pathway

Abstract

In recent years, the global incidence of chronic kidney disease (CKD) has been rising. As CKD progresses, it frequently involves inflammatory cell infiltration, contributing to renal fibrosis. Current research indicates that abnormalities in lipid metabolism play a role in this fibrotic process. However, the specific effects of various dietary fatty acids on renal inflammation and fibrosis remains largely unexplored. Our study demonstrates that dietary intake of omega-3 polyunsaturated fatty acids can inhibit macrophage activation and infiltration in a mouse model of unilateral ureteral obstruction (UUO), thus reducing the severity of renal fibrosis. Omega-3 polyunsaturated fatty acids, particularly α-linolenic acid (α-LA), mitigate damage to HK-2 cells and macrophages by targeting the JAG1-NOTCH1/2 pathway and by downregulating the expression of the chemokine MCP-1 and its receptor CCR2. This modulation attenuates macrophage activation and infiltration, reducing the inflammatory response. Furthermore, these fatty acids inhibit fibroblast chemotaxis, reduce fibroblast activation, and mitigate the deposition of extracellular matrix (ECM), thus slowing the progression of renal fibrosis. Our findings underscore the protective effects of omega-3 polyunsaturated fatty acids, such as α-LA, in preventing injury, inhibiting macrophage activation, and alleviating fibrosis. These results suggests that adjusting the dietary balance of fatty acids may offer a promising strategy to enhance the efficacy of CKD treatment.