Hypertensive individuals are at greater risk for developing chronic kidney disease (CKD). Reducing proteinuria has been suggested as a possible therapeutic approach to treat CKD. However, the mechanisms underlying the development of proteinuria in hypertensive conditions are incompletely understood. Cardiac and vascular dysfunction is associated with changes in the -GlcNAcylation pathway in hypertensive models. We hypothesized that-GlcNAcylation is also involved in renal damage, especially development of proteinuria, associated with hypertension. Using the spontaneously hypertensive rat (SHR) model, we observed higher renal cortex -GlcNAcylation, glutamine-fructose aminotransferase (GFAT), and-GlcNAc transferase (OGT) protein expression, which positively correlated with proteinuria. Interestingly, this was observed in hypertensive, but not pre-hypertensive, rats. Pharmacological inhibition of GFAT decreased renal cortex -GlcNAcylation, proteinuria, and albuminuria in SHR. Using a proximal tubule cell line, we observed that increased-GlcNAcylation reduced megalin surface expression and albumin endocytosis , and the effects were correlated Moreover, megalin is -GlcNAcylated both and In conclusion, our results demonstrate a new mechanism involved in hypertension-associated proteinuria.