Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential...

Area of Science:

• Cell Biology
• Metabolic Diseases
• Molecular Biology

Background:

• Hyperglycemia is a hallmark of diabetes, linked to increased oxidative stress.
• Prostaglandins (PGs) are implicated in diabetic glomerular hyperfiltration.
• Mitochondrial reactive oxygen species (ROS) production is elevated in hyperglycemic conditions.

Purpose of the Study:

• To investigate the effect of mitochondrial ROS on cyclooxygenase-2 (COX-2) expression in human mesangial cells (HMCs).
• To elucidate the role of hyperglycemia-induced mitochondrial ROS in the pathogenesis of diabetic nephropathy.

Main Methods:

• Cultured human mesangial cells (HMCs) were exposed to high glucose concentrations.
• Mitochondrial function, ROS production, COX-2 mRNA and protein expression, and PGE2 synthesis were measured.
• Inhibitors of mitochondrial metabolism and specific protein overexpressions were used.
• COX-2 expression was also assessed in glomeruli of diabetic mice.
• The COX-2 gene promoter activity was analyzed using reporter assays.

Main Results:

• High glucose (30 mmol/l) significantly increased COX-2 mRNA, mitochondrial membrane potential, intracellular ROS, COX-2 protein, and PGE2 synthesis in HMCs.
• These effects were abolished by mitochondrial inhibitors or overexpression of protective proteins.
• Increased COX-2 expression was observed in diabetic mouse glomeruli.
• Hyperglycemia activated the COX-2 gene promoter, dependent on nuclear factor kappaB (NF-kappaB) binding sites.

Conclusions:

• Hyperglycemia elevates mitochondrial ROS production in HMCs.
• This ROS surge activates NF-kappaB, leading to COX-2 induction and increased PGE2 synthesis.
• The identified pathway involving mitochondrial ROS and COX-2 may play a critical role in diabetic nephropathy development.