O-GlcNAcylation in Renal (Patho)Physiology

Abstract

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.

Keywords: O-GlcNAc; O-GlcNAc transferase; O-GlcNAcase; O-GlcNAcylation; albuminuria; kidney; post-translational modification; renal disease.

Figure 1

O-GlcNAc cycling scheme. Upon entry in cells, glucose is rapidly phosphorylated to glucose-6-phosphate (Glucose-6P) by hexokinase (HK). Glucose-6P is isomerized by phosphoglucose isomerase (PGI), producing fructose-6-phosphate (Fructose-6P), a substrate for both phosphofructokinase (PFK) of the glycolytic pathway or glucosamine-fructose amino transferase (GFAT), the rate-limiting reaction of the hexosamine biosynthetic pathway (HBP). GFAT requires glutamine (Gln) as the amine donor for generating glucosamine-6-phosphate (GlcN-6P), which is then N-acetylated by glucosamine-6-phosphate N-acetyltransferase (GNA1), producing N-acetyl-glucosamine-6-phosphate (GlcNAc-6P). This step requires acetyl-CoA as the acetyl donor. GlcNAc-6P is transformed in GlcNAc-1P by phosphoacetylglucosamine mutase (PGM3). Using UTP as the nucleotide donor, UDP-N-acetylglucosamine pyrophosphorylase (UAP1) produces uridine-diphosphate N-acetyl glucosamine (UDP-GlcNAc). This molecule is the substrate of O-GlcNAc transferase (OGT) for protein O-GlcNAcylation by adding O-linked GlcNAc moieties at serine or threonine residues of target proteins. O-GlcNAcase (OGA) removes GlcNAc residues, counteracting OGT activity.

Figure 2

Proposed model. The kidneys are possible targets of acute (ischemia-reperfusion injury, nephrotoxic agents) or chronic (diabetes, hypertension) insults. Renal O-GlcNacylation is associated with different outcomes in these conditions: acute increases in O-GlcNAcylation are associated with stress response, decreased apoptosis, and oxidative stress, reducing renal damage; chronic increases in renal O-GlcNAcylation observed in diabetes and hypertension are associated with mesangial expansion, proteinuria, and renal fibrosis, inducing the progression of renal diseases.