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Oxidative stress mediates activation of NF‐κB and contributes to pathogenesis of streptozotocin‐induced diabetes
Author(s) -
Kang YuMing,
Qin DaNian,
Elks Carrie,
Francis Joseph
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.990.9
Subject(s) - pyrrolidine dithiocarbamate , streptozotocin , endocrinology , medicine , oxidative stress , superoxide , chemistry , reactive oxygen species , proinflammatory cytokine , nadph oxidase , apocynin , pathogenesis , diabetes mellitus , nf κb , inflammation , biochemistry , enzyme
Basal neuronal activity in the PVN of diabetic rats is increased; however, the mechanism is not known. We hypothesized that reactive oxygen species (ROS) may activate NF‐κB in cardiovascular regions of the brain and induce downstream synthesis of excitatory elements including pro‐inflammatory cytokines (PICs) in progression of diabetes. Sprague‐Dawley rats were injected with streptozotocin (STZ, 65 mg/kg, ip) to induce diabetes, and treated for 4 weeks with a continuous intracerebroventricular (ICV) infusion of NF‐κB inhibitor pyrrolidine dithiocarbamate (PDTC, 5µg/h), or tempol (TEMP, 80µg/hr), a superoxide scavenger, or vehicle. There were higher plasma levels of glucose and PICs (TNF‐α, interleukin (IL)‐1β and IL‐6) and lower insulin in plasma and pancreatic islets in the STZ‐induced diabetic rats compared to control rats. Diabetic rats had high levels of Fra‐LI (an indicator of chronic neuronal activation), PICs, phosphorylated IKKβ (p‐IKKβ), superoxide and gp91 phox (a subunit of NAD(P)H oxidase) in the PVN. ICV treatments with PDTC or TEMP for 4 weeks reduced the plasma levels of PICs, expression of Fra‐LI, PICs, p‐IKKβ, superoxide and gp91 phox in the PVN of the STZ‐induced diabetic rats. These findings suggest that ROS mediate activation of NF‐κB in the PVN and contribute to pathogenesis of diabetes. Supported by NIH HL‐080544.