Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding

Significance Chronic kidney disease (CKD) remains a major health concern worldwide, affecting ∼10% of the population. Previous genome-wide association studies have identified many genes associated with CKD, but conclusive demonstrations of their roles in kidney function remain largely unexplored. Here, we identify the mechanistic basis of one such gene by creating mice deficient forGalnt11 . We demonstrate that Galnt11 influences kidney function by site-specific modification of the endocytosis receptor megalin within the proximal tubules of the kidney. Loss ofGalnt11 results in reduced megalin-mediated ligand binding and an age-related reduction in megalin levels, resulting in low-molecular-weight proteinuria. Our results identify a factor required for proper kidney function and provide insight into its association with CKD.