Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of CKD

Abstract

ABSTRACT Fetal kidney development is characterized by increased uptake of glucose, ATP production by glycolysis, and upregulation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1 alpha (HIF-1α), which (acting in concert) promote nephrogenesis in a hypoxic low–tubular-workload environment. By contrast, the healthy adult kidney is characterized by upregulation of sirtuin-1 and adenosine monophosphate–activated protein kinase, which enhances ATP production through fatty acid oxidation to fulfill the needs of a normoxic high–tubular-workload environment. During stress or injury, the kidney reverts to a fetal signaling program, which is adaptive in the short term, but is deleterious if sustained for prolonged periods when both oxygen tension and tubular workload are heightened. Prolonged increases in glucose uptake in glomerular and proximal tubular cells lead to enhanced flux through the hexosamine biosynthesis pathway; its end product—uridine diphosphate N-acetylglucosamine—drives the rapid and reversible O-GlcNAcylation of thousands of intracellular proteins, typically those that are not membrane-bound or secreted. Both O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O-GlcNAcylation is regulated only by O-GlcNAc transferase and O-GlcNAcase, which adds or removes N-acetylglucosamine, respectively, from target proteins. Diabetic and nondiabetic CKD is characterized by fetal reprogramming (with upregulation of mTOR and HIF-1α) and increased O-GlcNAcylation, both experimentally and clinically. Augmentation of O-GlcNAcylation in the adult kidney enhances oxidative stress, cell cycle entry, apoptosis, and activation of proinflammatory and profibrotic pathways, and it inhibits megalin-mediated albumin endocytosis in glomerular mesangial and proximal tubular cells—effects that can be aggravated and attenuated by augmentation and muting of O-GlcNAcylation, respectively. In addition, drugs with known nephroprotective effects—angiotensin receptor blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors—are accompanied by diminished O-GlcNAcylation in the kidney, although the role of such suppression in mediating their benefits has not been explored. The available evidence supports further work on the role of uridine diphosphate N-acetylglucosamine as a critical nutrient surplus sensor (acting in concert with upregulated mTOR and HIF-1α signaling) in the development of diabetic and nondiabetic CKD.