Serum fibrinogen-like protein 2 is associated with diabetic nephropathy severity and modulates high glucose-induced tubular dysfunction via Akt-FoxO1 signaling.

Diabetic nephropathy (DN) is a major cause of chronic kidney disease, and sensitive biomarkers of early tubular injury remain limited. Fibrinogen-like protein 2 (FGL2) has been implicated in inflammation and fibrosis, but its clinical significance and mechanistic role in DN are unclear. Serum FGL2 levels were measured in 105 patients with T2DM stratified by albuminuria and in 110 healthy controls, and its associations with metabolic parameters, renal injury, inflammation, and fibrosis were analyzed. In vitro, HK-2 cells were exposed to high glucose, and FGL2 was silenced using siRNA to assess effects on PI3K/Akt-FoxO1 signaling, cell viability, apoptosis, oxidative stress, and ECM remodeling. Pathway specificity was confirmed using a PI3K/Akt inhibitor. Serum FGL2 levels were higher in patients with T2DM than in controls and increased progressively with the severity of albuminuria. Circulating FGL2 positively correlated with glycemic indices, insulin resistance, lipid parameters, renal tubular injury markers (NGAL, KIM-1), inflammatory cytokines (TNF-α, IL-6), and fibrotic mediators (TGF-β1, CTGF). High glucose induced FGL2 expression in HK-2 cells in a dose-dependent manner. Silencing FGL2 enhanced Akt and FoxO1 phosphorylation, improved cell viability, reduced apoptosis, attenuated oxidative stress, restored antioxidant enzyme activity, and suppressed ECM-related gene and protein expression. These protective effects were reversed by PI3K/Akt inhibition. Serum FGL2 is elevated in patients with T2DM and correlates with the severity of renal injury, while mechanistically contributing to high glucose-induced tubular dysfunction via the PI3K/Akt-FoxO1 signaling pathway.