Marine n-3 fatty acids protect against renal function deterioration in diabetic patients by modulating lipoproteins and promoting cholesterol efflux

• Plasma n-3 PUFAs were associated with a 22% lower risk of developing CKD in diabetes. • Marine n-3 PUFA supplementation dose-dependently increase eGFR in diabetes. • Marine n-3 PUFA was associated with a lower risk of rapid decline in renal function. • The protective effect of n-3 PUFA on renal function was mediated by HDL-4-ApoA2. • n-3 PUFAs promoted renal cholesterol efflux by activating Sirt-1-PGC1-α-ABCA1 pathway. Marine n-3 polyunsaturated fatty acids (PUFAs) are proposed to have ameliorative effects on kidney function, but their role in type 2 diabetes (T2D)-related kidney disease remains uncertain. In this study, we assessed the protective effect of marine n-3 PUFAs against worsening renal function in T2D patients and explored the underlying mechanisms. Individuals with T2D in UK biobank were included to examine associations between circulating fatty acids and incident chronic kidney disease (CKD). The PNMD trial (NCT03708887) is a 14-month randomized, double-blind, placebo-controlled trial evaluating dose-dependent effects of marine n-3 PUFAs on renal function in T2D. In a cohort of 5,856 diabetic patients, higher plasma levels of n-3 PUFAs were associated with a 22% reduction in the risk of developing CKD. RCT involving 415 T2D patients reported that high-dose n-3 PUFA (3 g/day) supplementation significantly improved estimated glomerular filtration rate (eGFR) compared with placebo. The protective effect of n-3 PUFA supplementation against worsening renal function among T2D patients was primarily mediated by HDL-4-Apo-A2, a key subclass of high-density lipoproteins and was more pronounced in patients with the Apo-A1 related rs10419198 TT/CT genotype. Using the db/db /fat-1 transgenic mice, we unraveled endogenous n-3 PUFAs advances renal function by modulating lipid metabolism and promoting cholesterol efflux through the Sirt1-PGC1α-ABCA1 pathway. These findings provide novel insights into protective role of marine n-3 PUFAs in impaired preserving kidney function in T2D, underscoring their potential as a therapeutic strategy for diabetic kidney disease.