PMID- 37340541
OWN - NLM
STAT- MEDLINE
DCOM- 20230904
LR  - 20231018
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 34
IP  - 9
DP  - 2023 Sep 1
TI  - Fetal Reprogramming of Nutrient Surplus Signaling, O-GlcNAcylation, and the 
      Evolution of CKD.
PG  - 1480-1491
LID - 10.1681/ASN.0000000000000177 [doi]
AB  - 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 alpha ), 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 alpha ) 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 alpha signaling) in the development of diabetic and 
      nondiabetic CKD.
CI  - Copyright (c) 2023 The Author. Published by Wolters Kluwer Health, Inc. on behalf 
      of the American Society of Nephrology.
FAU - Packer, Milton
AU  - Packer M
AUID- ORCID: 0000-0003-1828-2387
AD  - Baylor Heart and Vascular Institute , Dallas , Texas and Imperial College , 
      London , United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20230621
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - V956696549 (Acetylglucosamine)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - 58-98-0 (Uridine Diphosphate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
SB  - IM
MH  - Humans
MH  - Acetylglucosamine/metabolism
MH  - *Diabetes Mellitus
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Nutrients
MH  - Glucose/metabolism
MH  - Uridine Diphosphate/metabolism
MH  - Adenosine Triphosphate/metabolism
MH  - *Renal Insufficiency, Chronic
MH  - Protein Processing, Post-Translational
PMC - PMC10482065
COIS- During the past three years, M. Packer reported personal fees for consulting from 
      Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, 
      Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, 
      Relypsa, and Salamandra. M. Packer also reports Consultancy: Altimmune, Ardelyx, 
      Regeneron, and Relypsa.
EDAT- 2023/06/21 06:42
MHDA- 2023/09/04 06:43
PMCR- 2024/09/01
CRDT- 2023/06/21 00:03
PHST- 2023/04/30 00:00 [received]
PHST- 2023/06/07 00:00 [accepted]
PHST- 2024/09/01 00:00 [pmc-release]
PHST- 2023/09/04 06:43 [medline]
PHST- 2023/06/21 06:42 [pubmed]
PHST- 2023/06/21 00:03 [entrez]
AID - 00001751-202309000-00005 [pii]
AID - JASN-2023-000597 [pii]
AID - 10.1681/ASN.0000000000000177 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2023 Sep 1;34(9):1480-1491. doi: 10.1681/ASN.0000000000000177. 
      Epub 2023 Jun 21.