Endothelial Ffar4 protects against diabetic kidney disease by potentiating endogenous retinoic acid metabolism

Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes and remains the primary cause of kidney failure worldwide, and a complex interaction of genetic and environmental dietary factors may be involved. Free fatty acid receptor 4 (Ffar4) may serve as a link between the genetic and dietary aspects of DKD progression; however, its role in DKD remains unclear. Ffar4-mediated DKD protection was evaluated using comprehensive genetic models. In addition, the effects of Ffar4 on glomerular inflammation and endothelial injury in mice were evaluated in vivo and in vitro, and the regulation of the Aldh1a1 gene by Ffar4 to maintain endogenous retinoic acid (RA) metabolic balance and related signaling pathways in the glomeruli was investigated. We found that Ffar4 expression was decreased in diabetes and was associated with renal complications. Conventional and endothelial-specific Ffar4 knockout exacerbated DKD, whereas endothelial-specific Ffar4 overexpression improved renal function. Mechanistically, Ffar4 regulated endogenous RA metabolism in the glomeruli through the Atf4–Aldh1a1 pathway. RA supplementation partially reversed DKD progression in endothelial-specific Ffar4 knockout mice. Taken together, these findings revealed a novel role of Ffar4 in potentiating endogenous RA production and delaying the progression of DKD-related multi-dysfunction.