PMID- 33192538
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201117
IS  - 1664-042X (Print)
IS  - 1664-042X (Electronic)
IS  - 1664-042X (Linking)
VI  - 11
DP  - 2020
TI  - OGT-Mediated KEAP1 Glycosylation Accelerates NRF2 Degradation Leading to High 
      Phosphate-Induced Vascular Calcification in Chronic Kidney Disease.
PG  - 1092
LID - 10.3389/fphys.2020.01092 [doi]
LID - 1092
AB  - Unraveling the complex regulatory pathways that mediate the effects of phosphate 
      on vascular smooth muscle cells (VSMCs) may provide novel targets and therapies 
      to limit the destructive effects of vascular calcification (VC) in patients with 
      chronic kidney disease (CKD). Our previous studies have highlighted several 
      signaling networks associated with VSMC autophagy, but the underlying mechanisms 
      remain poorly understood. Thereafter, the current study was performed to 
      characterize the functional relevance of O-linked N-acetylglucosamine (GlcNAc) 
      transferase (OGT) in high phosphate-induced VC in CKD settings. We generated VC 
      models in 5/6 nephrectomized rats in vivo and VSMC calcification models in vitro. 
      Artificial modulation of OGT (knockdown and overexpression) was performed to 
      explore the role of OGT in VSMC autophagy and VC in thoracic aorta, and in vivo 
      experiments were used to substantiate in vitro findings. Mechanistically, 
      co-immunoprecipitation (Co-IP) assay was performed to examine interaction between 
      OGT and kelch like ECH associated protein 1 (KEAP1), and in vivo ubiquitination 
      assay was performed to examine ubiquitination extent of nuclear factor erythroid 
      2-related factor 2 (NRF2). OGT was highly expressed in high phosphate-induced 5/6 
      nephrectomized rats and VSMCs. OGT silencing was shown to suppress high 
      phosphate-induced calcification of VSMCs. OGT enhances KEAP1 glycosylation and 
      thereby results in degradation and ubiquitination of NRF2, concurrently 
      inhibiting VSMC autophagy to promote VSMC calcification in 5/6 nephrectomized 
      rats. OGT inhibits VSMC autophagy through the KEAP1/NRF2 axis and thus 
      accelerates high phosphate-induced VC in CKD.
CI  - Copyright (c) 2020 Xu, Du, Sheng, Li, Qiu, Tian and Yao.
FAU - Xu, Tian-Hua
AU  - Xu TH
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Du, Yinke
AU  - Du Y
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Sheng, Zitong
AU  - Sheng Z
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Li, Yue
AU  - Li Y
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Qiu, Xiaobo
AU  - Qiu X
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Tian, Binyao
AU  - Tian B
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Yao, Li
AU  - Yao L
AD  - Department of Nephrology, The First Hospital of China Medical University, 
      Shenyang, China.
LA  - eng
PT  - Journal Article
DEP - 20201026
PL  - Switzerland
TA  - Front Physiol
JT  - Frontiers in physiology
JID - 101549006
PMC - PMC7649800
OTO - NOTNLM
OT  - O-linked N-acetylglucosamine transferase
OT  - autophagy
OT  - chronic kidney disease
OT  - high phosphorus
OT  - kelch like ECH associated protein 1
OT  - nuclear factor erythroid 2-related factor 2
OT  - vascular calcification
OT  - vascular smooth muscle cell
EDAT- 2020/11/17 06:00
MHDA- 2020/11/17 06:01
PMCR- 2020/10/26
CRDT- 2020/11/16 08:44
PHST- 2020/01/27 00:00 [received]
PHST- 2020/08/07 00:00 [accepted]
PHST- 2020/11/16 08:44 [entrez]
PHST- 2020/11/17 06:00 [pubmed]
PHST- 2020/11/17 06:01 [medline]
PHST- 2020/10/26 00:00 [pmc-release]
AID - 10.3389/fphys.2020.01092 [doi]
PST - epublish
SO  - Front Physiol. 2020 Oct 26;11:1092. doi: 10.3389/fphys.2020.01092. eCollection 
      2020.