Baylor Heart and Vascular Institute , Dallas , Texas and Imperial College , London , United Kingdom.
J Am Soc Nephrol. 2023 Sep 1;34(9):1480-1491. doi: 10.1681/ASN.0000000000000177. Epub 2023 Jun 21.
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-1 α ), 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-1 α ) 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-1 α signaling) in the development of diabetic and nondiabetic CKD.
胎儿肾脏发育的特点是葡萄糖摄取增加、糖酵解产生 ATP、哺乳动物雷帕霉素靶蛋白 (mTOR) 和低氧诱导因子 1α (HIF-1α) 上调，这些因素（协同作用）促进了缺氧、低肾小管工作量环境中的肾发生。相比之下，健康的成人肾脏的特点是 Sirtuin-1 和腺苷单磷酸激活蛋白激酶上调，通过脂肪酸氧化产生 ATP 以满足正常氧合、高肾小管工作量环境的需要。在应激或损伤期间，肾脏恢复到胎儿信号程序，该程序在短期内是适应性的，但如果持续时间延长，当氧张力和肾小管工作量都升高时，就会产生有害影响。肾小球和近端肾小管细胞中葡萄糖摄取的持续增加导致己糖胺生物合成途径通量增加；其终产物尿嘧啶二磷酸 N-乙酰葡萄糖胺驱动数千种细胞内蛋白的快速可逆 O-GlcNAc 化，通常是那些非膜结合或分泌的蛋白。O-GlcNAc 化和磷酸化都作用于丝氨酸/苏氨酸残基，但磷酸化受数百种特定的激酶和磷酸酶调节，而 O-GlcNAc 化仅受 O-GlcNAc 转移酶和 O-GlcNAcase 调节，它们分别向靶蛋白添加或去除 N-乙酰葡萄糖胺。糖尿病和非糖尿病 CKD 的特点是胎儿重编程（mTOR 和 HIF-1α 上调）和 O-GlcNAc 化增加，这在实验和临床中都得到了证实。成年肾脏中 O-GlcNAc 化的增强会增强氧化应激、细胞周期进入、细胞凋亡以及促炎和促纤维化途径的激活，并抑制肾小球系膜和近端肾小管细胞中 megalin 介导的白蛋白内吞作用——这些作用可以分别通过 O-GlcNAc 化的增强和沉默来加重和减轻。此外，具有已知肾脏保护作用的药物——血管紧张素受体阻滞剂、盐皮质激素受体拮抗剂和钠-葡萄糖共转运蛋白 2 抑制剂——在肾脏中伴随着 O-GlcNAc 化的减少，尽管这种抑制在介导其益处方面的作用尚未得到探索。现有证据支持进一步研究尿嘧啶二磷酸 N-乙酰葡萄糖胺作为关键营养过剩传感器的作用（与上调的 mTOR 和 HIF-1α 信号协同作用）在糖尿病和非糖尿病 CKD 发展中的作用。
