Hyaluronan increases glomerular cyclooxygenase-2 protein expression in a p38 MAP-kinase-dependent process.
BACKGROUND
Accumulation of the matrix glycosaminoglycan hyaluronan occurs in many types of renal injury but could follow any provision of hyaluronan substrate to the kidney, for example, through widespread use of supplementary glucosamine in osteoarthritic conditions. Hyaluronan can increase cyclooxygenase-2 (COX-2) protein and prostaglandin production. This effect was characterized in rat renal glomeruli to determine the cellular mechanism of activation.


METHODS
Isolated glomeruli were treated with purified hyaluronan (molecular mass 2 x 105 D) for up to 24 hours.


RESULTS
An increase in cyclooxygenase capacity and COX-2 protein was shown to follow the activation of p38-mitogen-activated protein (MAP) kinase and to be inhibited by a specific pyridinyl imadazole inhibitor (SB 202190). Hyaluronan-induced activation of cytosolic phospholipase A2 also was shown to be a p38 MAP kinase effect in these preparations. Prostaglandin production was inhibited by COX-2-specific non-steroidal anti-inflammatory compounds (NS-398 and celecoxib) but, as shown for many non-steroidal anti-inflammatory drugs (NSAIDs), an increase in COX-2 protein accompanied this inhibition.


CONCLUSIONS
We propose that these findings have clinical relevance. Prostaglandins have a number of important intrarenal regulatory effects leading to some debate over renal function with the use of NSAIDs. Where hyaluronan is increased, p38 MAP-kinase-dependent provision of prostaglandin substrate, via activation of cytosolic phospholipase A2, and a concomitant increase in cyclooxygenase-2 protein would raise renal prostaglandin levels. While NSAID treatment can prevent a rise in prostaglandin levels, it needs to be maintained to avoid possible exacerbation of pro-inflammatory conditions due to increased COX-2 protein levels.
Dunlop
Marjorie E
ME
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. medunlop@unimelb.edu.au
Muggli
Evelyne E
EE
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D006820:Hyaluronic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib