The NFAT5–AR Axis Is Associated with Hyperosmolarity, Renal Dysfunction, and Neutrophil-Related Inflammatory Markers in Diabetic Retinopathy

Diabetic retinopathy (DR) is a major microvascular complication of type 2 diabetes (T2D) and is strongly associated with chronic inflammation. Neutrophils contribute to this inflammatory milieu, and the hyperosmolar stress-responsive transcription factor NFAT5 and its downstream effector aldose reductase (AR) may play crucial roles in this process. NFAT5 regulates AR, which converts glucose to sorbitol; excessive sorbitol accumulation promotes endothelial and retinal cell damage. Given the links between NFAT5, metabolic stress and immune activation, dysregulation of the NFAT5-AR axis in neutrophils may contribute to DR pathophysiology. This study evaluated NFAT5 and AR expression in peripheral blood neutrophils from 150 individuals classified as nondiabetic (<i>n</i> = 50), T2D without DR (<i>n</i> = 50), or T2D with DR (<i>n</i> = 50). Clinical, metabolic, and ophthalmic assessments were performed, and neutrophils were isolated to quantify NFAT5 and AR via ELISA. Associations with renal function, plasma osmolarity (pOSM), and hematological inflammatory ratios (NLR, NMR, NPAR, and SII) were analyzed. T2D-DR subjects presented impaired renal parameters, increased pOSM, reduced eGFR, and elevated NLR and NPAR. NFAT5 and AR levels were significantly increased in T2D-DR neutrophils and correlated positively with pOSM and the inflammatory ratios, whereas NFAT5 correlated inversely with the eGFR. These findings suggest that activation of the NFAT5-AR pathway contributes to neutrophil-driven inflammatory and hyperosmolar dysregulation in T2D and may influence DR progression.