期刊
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
卷 463, 期 2, 页码 377-390出版社
SPRINGER
DOI: 10.1007/s00424-011-1047-x
关键词
BRIN-BD11 cells; beta-Cells; Rat pancreatic islet; Hypotonicity; H2O2; NAD(P)H oxidase; NOX; Insulin release
类别
资金
- Fonds Alphonse et Jean Forton
- Fonds de la Recherche Scientifique Medicale (FRSM) [3.4520.07]
- Fonds d' Encouragement a la Recherche (FER, ULB)
NAD(P)H oxidase (NOX)-derived H2O2 was recently proposed to act, in several cells, as the signal mediating the activation of volume-regulated anion channels (VRAC) under a variety of physiological conditions. The present study aims at investigating whether a similar situation prevails in insulin-secreting BRIN-BD11 and rat beta-cells. Exogenous H2O2 (100 to 200 mu M) at basal glucose concentration (1.1 to 2.8 mM) stimulated insulin secretion. The inhibitor of VRAC, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) inhibited the secretory response to exogenous H2O2. In patch clamp experiments, exogenous H2O2 was observed to stimulate NPPB-sensitive anion channel activity, which induced cell membrane depolarization. Exposure of the BRIN-BD11 cells to a hypotonic medium caused a detectable increase in intracellular level of reactive oxygen species (ROS) that was abolished by diphenyleneiodonium chloride (DPI), a universal NOX inhibitor. NOX inhibitors such as DPI and plumbagin nearly totally inhibited insulin release provoked by exposure of the BRIN-BD11 cells to a hypotonic medium. Preincubation with two other drugs also abolished hypotonicity-induced insulin release and reduced basal insulin output: 1) N-acetyl-L-cysteine (NAC), a glutathione precursor that serves as general antioxidant and 2) betulinic acid a compound that almost totally abolished NOX4 expression. As NPPB, each of these inhibitors (DPI, plumbagin, preincubation with NAC or betulinic acid) strongly reduced the volume regulatory decrease observed following a hypotonic shock, providing an independent proof that VRAC activation is mediated by H2O2. Taken together, these data suggest that NOX-derived H2O2 plays a key role in the insulin secretory response of BRIN-BD11 and native beta-cells to extracellular hypotonicity.
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