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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts beta-Cell Function and Survival

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Author(s):
Vilas-Boas, Eloisa A. [1, 2] ; Carlein, Christopher [2] ; Nalbach, Lisa [3] ; Almeida, Davidson C. [4] ; Ampofo, Emmanuel [3] ; Carpinelli, Angelo R. [1] ; Roma, Leticia P. [2] ; Ortis, Fernanda [4]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508000 Sao Paulo - Brazil
[2] Saarland Univ, Ctr Human & Mol Biol ZHMB, Dept Biophys, D-66424 Homburg - Germany
[3] Saarland Univ, Inst Clin & Expt Surg, D-66424 Homburg - Germany
[4] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, BR-05508000 Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: ANTIOXIDANTS; v. 10, n. 8 AUG 2021.
Web of Science Citations: 0
Abstract

In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in beta-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O-2(center dot-) production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H2O2 sensor, we show, for the first time, a transient increase of cytosolic/nuclear H2O2 in islet cells between 4 and 5 h during cytokine exposure. The H2O2 increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca2+ depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H2O2 production. As early NOX2-driven ROS production impacts beta-cells' function and survival during insulitis, NOX2 might be a potential target for designing therapies against early beta-cell dysfunction in the context of T1D onset. (AU)

FAPESP's process: 17/26339-5 - Involvement of NADPH oxidase isoforms in the dysfunction of insulin secreting cells exposed to pro-inflammatory cytokines
Grantee:Angelo Rafael Carpinelli
Support Opportunities: Regular Research Grants
FAPESP's process: 20/06184-0 - Characterization of the expression of NADPH oxidase isoforms in pancreatic beta cells and its modulation by proinflammatory cytokines
Grantee:Angelo Rafael Carpinelli
Support Opportunities: Regular Research Grants
FAPESP's process: 17/04580-2 - Study of pancreatic beta cell demise: role of NF-kB, HNF4a and IL6 in the Diabetes mellitus development
Grantee:Fernanda Ortis
Support Opportunities: Regular Research Grants
FAPESP's process: 13/08769-1 - The role of NAD(P)H oxidase in the physiological and pathological molecular mechanisms of insulin secreting cells
Grantee:Angelo Rafael Carpinelli
Support Opportunities: Research Projects - Thematic Grants