PMID- 37822879
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231030
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 14
DP  - 2023
TI  - Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis 
      of human glomerular mesangial cells by alleviating FOXO6 m6A modification via 
      YTHDF3-dependent mechanisms.
PG  - 1260300
LID - 10.3389/fphar.2023.1260300 [doi]
LID - 1260300
AB  - Background: N6-methyladenosine (m6A) is a prevalent post-transcriptional 
      modification presented in messenger RNA (mRNA) of eukaryotic organisms. Chronic 
      glomerulonephritis (CGN) is characterised by excessive proliferation and 
      insufficient apoptosis of human glomerular mesangial cells (HGMCs) but its 
      underlying pathogenesis remains undefined. Moreover, the role of m6A in CGN is 
      poorly understood. Methods: The total level of m6A modification was detected 
      using the m6A quantification assay (Colorimetric). Cell proliferation was 
      assessed by EdU cell proliferation assay, and cell apoptosis was detected by flow 
      cytometry. RNA sequencing was performed to screen the downstream target of fat 
      mass and obesity-associated protein (FTO). MeRIP-qPCR was conducted to detect the 
      m6A level of forkhead box o6 (FOXO6) in HGMCs. RIP assay was utilized to indicate 
      the targeting relationship between YTH domain family 3 (YTHDF3) and FOXO6. 
      Actinomycin D assay was used to investigate the stability of FOXO6 in HGMCs. 
      Results: The study found that the expression of FTO was significantly reduced in 
      lipopolysaccharide (LPS)-induced HGMCs and renal biopsy samples of patients with 
      CGN. Moreover, FTO overexpression and knockdown could regulate the proliferation 
      and apoptosis of HGMCs. Furthermore, RNA sequencing and cellular experiments 
      revealed FOXO6 as a downstream target of FTO in regulating the proliferation and 
      apoptosis of HGMCs. Mechanistically, FTO overexpression decreases the level of 
      FOXO6 m6A modification and reduces the stability of FOXO6 mRNA in a 
      YTHDF3-dependent manner. Additionally, the decreased expression of FOXO6 inhibits 
      the PI3K/AKT signaling pathway, thereby inhibiting the proliferation and 
      promoting apoptosis of HGMCs. Conclusion: This study offers insights into the 
      mechanism through which FTO regulates the proliferation and apoptosis of HGMCs by 
      mediating m6A modification of FOXO6 mRNA. These findings also suggest FTO as a 
      potential diagnostic marker and therapeutic target for CGN.
CI  - Copyright (c) 2023 Zhuang, Liu, Wei and Gao.
FAU - Zhuang, Xingxing
AU  - Zhuang X
AD  - Department of Pharmacy, Chaohu Hospital of Anhui Medical University, Chaohu, 
      China.
AD  - Department of Pharmacy, The First Affiliated Hospital of Anhui University of 
      Chinese Medicine, Hefei, China.
FAU - Liu, Tao
AU  - Liu T
AD  - Department of Pharmacy, The First Affiliated Hospital of Anhui University of 
      Chinese Medicine, Hefei, China.
FAU - Wei, Liangbing
AU  - Wei L
AD  - Department of Pharmacy, The First Affiliated Hospital of Anhui University of 
      Chinese Medicine, Hefei, China.
FAU - Gao, Jiarong
AU  - Gao J
AD  - Department of Pharmacy, The First Affiliated Hospital of Anhui University of 
      Chinese Medicine, Hefei, China.
LA  - eng
PT  - Journal Article
DEP - 20230926
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC10562590
OTO - NOTNLM
OT  - FOXO6
OT  - FTO
OT  - cell apoptosis
OT  - cell proliferation
OT  - glomerular mesangial cells
OT  - m6A modification
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/10/12 06:43
MHDA- 2023/10/12 06:44
PMCR- 2023/09/26
CRDT- 2023/10/12 04:13
PHST- 2023/07/17 00:00 [received]
PHST- 2023/09/15 00:00 [accepted]
PHST- 2023/10/12 06:44 [medline]
PHST- 2023/10/12 06:43 [pubmed]
PHST- 2023/10/12 04:13 [entrez]
PHST- 2023/09/26 00:00 [pmc-release]
AID - 1260300 [pii]
AID - 10.3389/fphar.2023.1260300 [doi]
PST - epublish
SO  - Front Pharmacol. 2023 Sep 26;14:1260300. doi: 10.3389/fphar.2023.1260300. 
      eCollection 2023.