Hyaluronan increases glomerular cyclooxygenase-2 protein expression in a p38 MAP-kinase-dependent process

Area of Science:

• Nephrology
• Molecular Biology
• Pharmacology

Background:

• Hyaluronan accumulation in renal injury can increase cyclooxygenase-2 (COX-2) and prostaglandin production.
• This effect may be exacerbated by widespread glucosamine use for osteoarthritis.
• The cellular mechanism of hyaluronan-induced COX-2 activation in the kidney was investigated.

Purpose of the Study:

• To characterize the cellular mechanism by which hyaluronan activates cyclooxygenase-2 (COX-2) and prostaglandin production in rat renal glomeruli.
• To investigate the role of p38 mitogen-activated protein (MAP) kinase in this process.
• To explore the implications for non-steroidal anti-inflammatory drug (NSAID) use in conditions with elevated hyaluronan.

Main Methods:

• Isolated rat glomeruli were incubated with purified hyaluronan.
• Changes in COX-2 protein, prostaglandin production, and p38 MAP kinase activation were measured.
• Specific inhibitors of p38 MAP kinase and COX-2 were used to elucidate the pathway.

Main Results:

• Hyaluronan exposure increased COX-2 protein and prostaglandin production in glomeruli.
• This increase was dependent on the activation of p38 MAP kinase.
• Hyaluronan also activated cytosolic phospholipase A2, a p38 MAP kinase-dependent effect.
• While NSAIDs inhibited prostaglandin production, they increased COX-2 protein levels.

Conclusions:

• Hyaluronan increases renal prostaglandin levels through p38 MAP kinase-dependent activation of cytosolic phospholipase A2 and increased COX-2 protein.
• This pathway has clinical relevance, particularly concerning NSAID use in renal conditions with elevated hyaluronan.
• Sustained NSAID treatment may be necessary to prevent exacerbation of inflammation due to increased COX-2 protein.