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Am J Physiol Endocrinol Metab 292: E1543-E1554, 2007. First published January 30, 2007; doi:10.1152/ajpendo.00620.2006
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Protective role for nitric oxide during the endoplasmic reticulum stress response in pancreatic beta-cells

Kajorn Kitiphongspattana,1 Tarannum A. Khan,2 Katrin Ishii-Schrade,2 Michael W. Roe,1 Louis H. Philipson,1 and H. Rex Gaskins2,3,4,5

1Department of Medicine, The University of Chicago, Chicago; and Departments of 2Animal Sciences and 3Pathobiology, 4Division of Nutritional Sciences, and 5Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois

Submitted 16 November 2006 ; accepted in final form 3 January 2007

Higher requirements for disulfide bond formation in professional secretory cells may affect intracellular redox homeostasis, particularly during an endoplasmic reticulum (ER) stress response. To assess this hypothesis, we investigated the effects of the ER stress response on the major redox couple (GSH/GSSG), endogenous ROS production, expression of genes involved in ER oxidative protein folding, general antioxidant defense, and thiol metabolism by use of the well-validated MIN6 beta-cell as a model and mouse islets. The data revealed that glucose concentration-dependent decreases in the GSH/GSSG ratio were further decreased significantly by ER-derived oxidative stress induced by inhibiting ER-associated degradation with the specific proteasome inhibitor lactacystin (10 µM) in mouse islets. Notably, minimal cell death was observed during 12-h treatments. This was likely attributed to the upregulation of genes encoding the rate limiting enzyme for glutathione synthesis ({gamma}-glutamylcysteine ligase), as well as genes involved in antioxidant defense (glutathione peroxidase, peroxiredoxin-1) and ER protein folding (Grp78/BiP, PDI, Ero1). Gene expression and reporter assays with a NO synthase inhibitor (N{omega}-nitro-L-arginine methyl ester, 1–10 mM) indicated that endogenous NO production was essential for the upregulation of several ER stress-responsive genes. Specifically, gel shift analyses demonstrate NO-independent binding of the transcription factor NF-E2-related factor to the antioxidant response element Gclc-ARE4 in MIN6 cells. However, endogenous NO production was necessary for activation of Gclc-ARE4-driven reporter gene expression. Together, these data reveal a distinct protective role for NO during the ER stress response, which helps to dissipate ROS and promote beta-cell survival.

endoplasmic reticulum-associated degradation; glutathione; proteasome


Address for reprint requests and other correspondence: H. R. Gaskins, Univ. of Illinois, 1207 W. Gregory Dr., Urbana, IL 61801 (e-mail: hgaskins{at}uiuc.edu)






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