Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the Evolution of Chronic Kidney Disease.

Fetal kidneys have increased uptake of glucose, ATP production by glycolysis, and upregulation of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α). These interacting processes promote nephrogenesis in a hypoxic low-tubular-workload environment. In contrast, the healthy adult kidney upregulates sirtuin-1 and adenosine monophosphate-activated protein kinase, which enhances ATP production through fatty-acid oxidation, in a normoxic high-tubular-workload environment. During stress or injury, the kidney reverts to a fetal signaling program that is adaptive in the short-term, but deleterious if sustained with heightened oxygen tension and tubular workloads. Prolonged increase in glucose uptake in glomerular and proximal tubular cells leads to enhanced flux through the hexosamine biosynthesis pathway. The endproduct - uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) - drives the rapid and reversible O-GlcNAcylation of thousands of intracellular proteins, most not membrane-bound or secreted. O-GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas hundreds of kinases and phosphatases regulate phosphorylation, only O-GlcNAc transferase and O-GlcNAcase, which add or remove O-GlcNAc from target proteins, regulate O-GlcNAcylation. Fetal reprogramming (upregulating mTOR and HIF-1α) and increased O-GlcNAcylation occur in diabetic and nondiabetic CKD, experimentally and clinically. Augmentation of O-GlcNAcylation in the adult kidney enhances oxidative stress, cell cycle entry, and apoptosis, activates proinflammatory and profibrotic pathways, and inhibits megalin-mediated albumin endocytosis in glomerular mesangial and proximal tubular cells, which muting of O-GlcNAcylation can aggravate and attenuate, respectively. Additionally, some nephroprotective drugs are associated with diminished O-GlcNAcylation in the kidney. Evidence supports further investigation of UDP-GlcNAc as a critical nutrient surplus sensor in the development of diabetic and nondiabetic CKD.