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

Abstract

Chronic kidney disease (CKD) affects more than 20 million Americans and ∼10% of the population worldwide. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of 1 GWAS-identified gene by creating mice deficient for <i>Galnt11</i>, which encodes a member of the enzyme family that initiates protein O-glycosylation, an essential posttranslational modification known to influence protein function and stability. We find that <i>Galnt11</i>-deficient mice display low-molecular-weight proteinuria and have specific defects in proximal tubule-mediated resorption of vitamin D binding protein, α₁-microglobulin, and retinol binding protein. Moreover, we identify the endocytic receptor megalin (LRP2) as a direct target of Galnt11 in vivo. Megalin in <i>Galnt11</i>-deficient mice displays reduced ligand binding and undergoes age-related loss within the kidney. Differential mass spectrometry revealed specific sites of Galnt11-mediated glycosylation within mouse kidney megalin/LRP2 that are known to be involved in ligand binding, suggesting that O-glycosylation directly influences the ability to bind ligands. In support of this, recombinant megalin containing these sites displayed reduced albumin binding in cells deficient for <i>Galnt11</i> Our results provide insight into the association between <i>GALNT11</i> and CKD, and identify a role for Galnt11 in proper kidney function.