Oxidative Stress and Diabetes
Jian Li
Beijing Institute of Geriatrics
Ministry of Health
Redox "rheostat“ in vascular cells
Reactive oxygen species (= ROS)
O2
O2-
H2 O2
acidic pH,
Superoxyde
Dismutase (SOD)
NADPH oxidase
Superoxide
anion
Hydrogen
peroxide
Proposed functions of ROS
killing of microorganisms
DNA damage
cancerogenesis
ageing
cell death
NO inactivation and peroxynitrite generation
regulation of cell growth and differentiation
regulation of cell function
oxygen sensing
activation of redox-sensitive transcription factors
activation of redox-sensitive second messenger systems
Where and why are reactive oxygen species generated?
Mitochondria
by-product of the oxidative metabolism
Phagocyte NADPH oxidase
microbial killing
NADPH oxidase of non-phagocytic cells
cell growth, cell signaling
NOX-type NADPH oxidases as superoxide-producing enzymes
The NOX family of NADPH oxidases
Review: Lambeth et al. Novel homologs of gp91phox.Trends in Biochemical Sciences 25: 459-461, 2000.
gp91phox
homology
EF-hands
Nox1 colon
Nox2 phagocytes
Nox3 inner ear
Nox4 kidney
Nox5 testis and lymphoid tissues
O2
O2-
NADPH
e-
Structure of the NAD(P)H oxidase
Characteristics of neutrophil and vascular NAD(P)H oxidase
NAD(P)H Oxidase Activation
Adenovirus-induced overexpression of PKC-β2 causes the membranous translocation of p47phox and p67phox
A model illustrating how increased ROS production in accumulated fat contributes to metabolic syndrome
Mechanism for increased ROS production induced by diabetes and insulin-resistant state
Linking various risk factors to ROS generation in the development of IDDM
Initiation and amplification of the immune/inflammatory response by ROS-induced NFκ B activation in β-cell death
Schematic illustration of ROS-mediated NFκB activation
Elevated glucose and FFA levels contribute to the pathophysiology of diabetes via the generation of ROS
The role of serine kinase activation in oxidative stress induced insulin resistance
Vascular effects of reactive oxygen species (ROS)
Modulation of cellular function by ROS in cardiovascular diseases
Potential role of NADPH oxidase in the pathogenesis of diabetic nephropathy
Effect of high glucose level and PMA on ROS production in aortic smooth muscle cells (A) and endothelial cells (B)
Effect of diphenylene iodonium on high glucose– or PMA-induced increase in ROS production in aortic smooth muscle cells (A) or endothelial cells (B)
PKC-β inhibition suppresses diabetes-induced O2- production
Redox-dependent signaling pathways by Ang II in vascular smooth muscle cells
Detection of intracellular production of reactive oxygen species.
A. Fluorescence microscopy visualization of ROS production in pericytes and smooth muscle cells. a: control;b: cells cultured in 25 mM glucose and AGE-Lys stimulated with Ang II;c and d : corresponding phase contrast microscopy. B. Pericytes cultured in the pro-diabetic environment, were loaded for 30 min at 37oC with 5mM DCF-DA .
The effect of high glucose concentration, AGE-Lys and their combination with Ang II on intracellular calcium [Ca2+]i
Detection of O2- production by dihydroethidium staining in mesangial cells overexpressing PKC-β2
Superoxide production in nonatherosclerotic
and atherosclerotic arteries
nonatherosclerotic arteries atherosclerotic arteries
Expression of NAD(P)H oxidase subunits in nonatherosclerotic and atherosclerotic arteries
In situ detection of superoxide in sham-operated and injured carotid arteries
Possible antioxidative agents for diabetic vascular complications
Thank you!