PMID- 34363947
OWN - NLM
STAT- MEDLINE
DCOM- 20210909
LR  - 20210909
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 174
DP  - 2021 Oct
TI  - The importance of aquaporin-8 for cytokine-mediated toxicity in rat 
      insulin-producing cells.
PG  - 135-143
LID - S0891-5849(21)00443-3 [pii]
LID - 10.1016/j.freeradbiomed.2021.08.003 [doi]
AB  - Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide 
      (H(2)O(2)) transport protein expressed in the mitochondrial and plasma membranes 
      of pancreatic beta-cells. AQP8 protein expression is low under physiological 
      conditions, but it increases after cytokine exposure both, in vitro and in vivo, 
      possibly related to a NF-kappaB consensus sequence in the promoter. AQP8 knockdown 
      (KD) insulin-producing RINm5F cells are particularly susceptible to 
      cytokine-mediated oxidative stress. Cytokine (a mixture of IL-1beta, TNF-alpha, and 
      IFN-gamma) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen 
      and nitrogen species (ROS and RNS), resulting in a significant loss of beta-cell 
      viability due to enhanced toxicity of the increased concentrations of H(2)O(2) 
      and hydroxyl radicals ((●)OH) in mitochondria of AQP8 KD cells. This viability 
      loss went along with increased caspase activities, reduced nitrite concentration 
      (representative of nitric oxide (NO(●)) accumulation) and increased lipid 
      peroxidation. The explanation for the increased toxicity of the proinflammatory 
      cytokines in AQP8 KD cells resides in the fact that efflux of the H(2)O(2) 
      generated during oxidative stress in the beta-cell mitochondria is hampered through 
      the loss of the peroxiporin channels in the mitochondrial membranes of the AQP8 
      KD cells. The increased proinflammatory cytokine toxicity due to loss of AQP8 
      expression in the KD beta-cell mitochondria is thus the result of increased rates of 
      apoptosis. This decreased cell viability is caused by increased levels of 
      oxidative stress along with a ferroptosis-mediated cell death component due to 
      decreased NO(●) generation.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Kruger, Christina
AU  - Kruger C
AD  - Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, 
      Germany.
FAU - Jorns, Anne
AU  - Jorns A
AD  - Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, 
      Germany.
FAU - Kaynert, Jonas
AU  - Kaynert J
AD  - Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, 
      Germany.
FAU - Waldeck-Weiermair, Markus
AU  - Waldeck-Weiermair M
AD  - Cardiovascular Division, Brigham and Women's Hospital, And Harvard Medical 
      School, Boston, MA, 02115, USA.
FAU - Michel, Thomas
AU  - Michel T
AD  - Cardiovascular Division, Brigham and Women's Hospital, And Harvard Medical 
      School, Boston, MA, 02115, USA.
FAU - Elsner, Matthias
AU  - Elsner M
AD  - Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, 
      Germany.
FAU - Lenzen, Sigurd
AU  - Lenzen S
AD  - Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, 
      Germany; Institute of Experimental Diabetes Research, Hannover Medical School, 
      30623, Hannover, Germany. Electronic address: lenzen.sigurd@mh-hannover.de.
LA  - eng
GR  - R01 HL152173/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210804
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Aquaporins)
RN  - 0 (Cytokines)
RN  - 0 (Insulin)
RN  - BBX060AN9V (Hydrogen Peroxide)
SB  - IM
MH  - Animals
MH  - *Aquaporins
MH  - Cytokines/genetics
MH  - Hydrogen Peroxide/metabolism/toxicity
MH  - Insulin/metabolism
MH  - *Insulin-Secreting Cells/metabolism
MH  - Rats
OTO - NOTNLM
OT  - Apoptosis
OT  - Aquaporin-8
OT  - Cytokines
OT  - Diabetes
OT  - Ferroptosis
OT  - Hydrogen peroxide
OT  - Nitric oxide
OT  - Pancreatic beta-cell
EDAT- 2021/08/08 06:00
MHDA- 2021/09/10 06:00
CRDT- 2021/08/07 20:13
PHST- 2021/06/18 00:00 [received]
PHST- 2021/07/20 00:00 [revised]
PHST- 2021/08/03 00:00 [accepted]
PHST- 2021/08/08 06:00 [pubmed]
PHST- 2021/09/10 06:00 [medline]
PHST- 2021/08/07 20:13 [entrez]
AID - S0891-5849(21)00443-3 [pii]
AID - 10.1016/j.freeradbiomed.2021.08.003 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2021 Oct;174:135-143. doi: 
      10.1016/j.freeradbiomed.2021.08.003. Epub 2021 Aug 4.