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 Galnt11, 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 Galnt11-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 Galnt11-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 Galnt11. Our results provide insight into the association between GALNT11 and CKD, and identify a role for Galnt11 in proper kidney function.

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney

“…reabsorption processes in the proximal tubule and regulation of urinary excretion of protein. 41 , 42 Most importantly, our analyses conducted across three independent datasets of human renal tissue (totalling 720 individuals) provide strong and consistent evidence for a positive association between renal expression of ACE2 and eGFR. Collectively, these data indicate that ACE2 is positively correlated with a measure of kidney function and are consistent with previous observations on i.e.…”

Hypertension and renin-angiotensin system blockers are not associated with expression of Angiotensin Converting Enzyme 2 (ACE2) in the kidney

“…Several of the ACE2 co-expressed renal genes (including LRP2, CUBN, SLC47A1, GALNT1) were associated with eGFR, albuminuria and/or the risk of chronic kidney disease in the genome-wide association studies 57-59 . While the inactivation, loss-of-function and/or drop in renal expression of most of these molecules is generally interpreted as detrimental to kidney health 47,48,53 , in our analyses the expression of these genes showed a positive association with the renal abundance of ACE2. Together with the directionally consistent positive association between renal expression of ACE2 and eGFR in two independent datasets our data point to the nephro-protective function of ACE2.…”

“…For example, LRP2 and CUBN encode megalin and cubilin – the receptors responsible for reabsorption of proteins, hormones, and vitamins in the proximal tubule and regulation of urinary excretion of protein 52 . Encoded by GALNT11, polypeptide N-Acetylgalactosaminyltransferase 11 acts a post-transcriptional modifier of LRP2, regulates its function as an endocytosis receptor and associates with proteinuria 53 . Klotho (a product of KL) operates as a multifunctional regulator of renal phosphate reabsorption, apoptosis, fibrosis, and cellular senescence; the renal depletion of KL plays a role in both acute kidney injury and chronic kidney disease 54,55 .…”

An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles

“…Surprisingly, we identified >150 glycosites on mature peptide hormones with many located in the receptor-interacting regions. O-glycans are known to modulate receptor functions, as first described for O-fucosylation of the Notch receptor 53 , and more recently for GalNAc-type O-glycosylation of the low-density lipoprotein receptor-related receptors 54 – 56 . However, to our knowledge, receptors recognizing protein/peptide ligands have not yet been described to exhibit specific recognition of O-glycosylated ligands, apart from the large families of lectin receptors that primarily recognize the glycans 57 .…”