PMID- 30134927
OWN - NLM
STAT- MEDLINE
DCOM- 20190117
LR  - 20220330
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Print)
IS  - 1076-1551 (Linking)
VI  - 24
IP  - 1
DP  - 2018 Aug 14
TI  - Reversal of angiotensin ll-induced beta-cell dedifferentiation via inhibition of 
      NF-kappab signaling.
PG  - 43
LID - 10.1186/s10020-018-0044-3 [doi]
LID - 43
AB  - BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by pancreatic beta-cell 
      failure, which arises from metabolic stress and results in beta cell 
      dedifferentiation, leading to beta-cell death. Pathological activation of the 
      renin-angiotensin system (RAS) contributes to increase cell stress, while RAS 
      intervention reduces the onset of T2DM in high-risk populations and promotes 
      insulin secretion in rodents. In this study, we investigated whether and how RAS 
      induces beta-cell dedifferentiation and the mechanism underlying this process. 
      METHODS: In vitro, with the methods of quantitative real-time reverse 
      transcriptase-PCR (qRT-PCR) and western blotting, we examined the change of cell 
      identity-related gene expression, progenitor like gene expression, cellular 
      function, and nuclear factor kappa b (NF-kappab) signaling activity in beta cell lines 
      after exposure to angiotensin II (AngII) and disruption of RAS. In vivo, parallel 
      studies were performed using db/db mice. Related protein expression was detected 
      by Immunofluorescence analysis. RESULT: Activation of RAS induced 
      dedifferentiation and impaired insulin secretion, eventually leading to beta-cell 
      failure. Mechanistically, Angll induced beta-cell dedifferentiation via NF-kappab 
      signaling, while treatment with lrbesartan and sc-514 reversed the progenitor 
      state of beta cells. CONCLUSION: The present study found that RAS might induce 
      beta-cell dedifferentiation via angiotensin II receptor type 1 activation, which was 
      promoted by NF-kappab signaling. Therefore, blocking RAS or NF-kb signaling 
      efficiently reversed the dedifferentiated status of beta cells, suggesting a 
      potential therapy for patients with type 2 diabetes.
FAU - Chen, Hong
AU  - Chen H
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Zhou, Wenjun
AU  - Zhou W
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Ruan, Yuting
AU  - Ruan Y
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Yang, Lei
AU  - Yang L
AD  - Department of Nephrology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Xu, Ningning
AU  - Xu N
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Chen, Rongping
AU  - Chen R
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Yang, Rui
AU  - Yang R
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China.
FAU - Sun, Jia
AU  - Sun J
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China. 
      sunjia@smu.edu.cn.
FAU - Zhang, Zhen
AU  - Zhang Z
AUID- ORCID: 0000-0002-1252-7972
AD  - Department of Endocrinology, Zhujiang Hospital, Southern Medical University, 253, 
      Gongyedadao Middle, Guangzhou, Guangdong, 510282, People's Republic of China. 
      zzhen311@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180814
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - 0 (Insulin)
RN  - 0 (NF-kappa B)
RN  - 11128-99-7 (Angiotensin II)
SB  - IM
MH  - Angiotensin II/*pharmacology
MH  - Animals
MH  - Cell Dedifferentiation/*drug effects
MH  - Cell Line, Tumor
MH  - Diabetes Mellitus, Type 2/metabolism
MH  - Gene Expression/drug effects
MH  - Insulin/metabolism
MH  - Insulin-Secreting Cells/*drug effects/metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/*antagonists & inhibitors/metabolism
MH  - Rats
MH  - Renin-Angiotensin System
MH  - Signal Transduction/drug effects
PMC - PMC6092859
OTO - NOTNLM
OT  - Angiotensin ll
OT  - NF-kappab
OT  - Renin-angiotensin system
OT  - Type 2 diabetes
OT  - beta-Cell dedifferentiation
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All the animal protocols were 
      approved by the Ethics Committee for the use of Experimental Animals at the 
      Southern Medical University. CONSENT FOR PUBLICATION: Not applicable COMPETING 
      INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S 
      NOTE: Springer Nature remains neutral with regard to jurisdictional claims in 
      published maps and institutional affiliations.
EDAT- 2018/08/24 06:00
MHDA- 2019/01/18 06:00
PMCR- 2018/08/14
CRDT- 2018/08/24 06:00
PHST- 2018/04/03 00:00 [received]
PHST- 2018/07/30 00:00 [accepted]
PHST- 2018/08/24 06:00 [entrez]
PHST- 2018/08/24 06:00 [pubmed]
PHST- 2019/01/18 06:00 [medline]
PHST- 2018/08/14 00:00 [pmc-release]
AID - 10.1186/s10020-018-0044-3 [pii]
AID - 44 [pii]
AID - 10.1186/s10020-018-0044-3 [doi]
PST - epublish
SO  - Mol Med. 2018 Aug 14;24(1):43. doi: 10.1186/s10020-018-0044-3.