Hyaluronan-induced cyclooxygenase-2 expression promotes thromboxane A2 production by renal cells.
BACKGROUND
Matrix degradation products such as fragmented hyaluronan (HA) display important proinflammatory effects on renal tubular epithelial cells (TECs) and macrophages (MPhis). We hypothesized that HA could up-regulate cyclooxygenase type 2 (COX-2) in these cells and that the subsequent production of thromboxane A2 (TXA2) could play a role in inflammatory renal lesions.


METHODS
We used an in vitro approach to examine the expression of COX-1 and COX-2 and the production of TXA2 in response to fragments of HA. COX-2 mRNA, protein, and the resulting TXA2 production were measured in CD44-positive, HA-responsive cells lines of TECs and MPhi. COX-2 mRNA was also measured in vivo in MRL-Faslpr mice and in mice with anti-glomerular basement membrane (anti-GBM) nephritis.


RESULTS
In TECs and MPhis, HA increased the steady-state COX-2 mRNA and protein levels markedly, whereas COX-1 mRNA levels did not change. The HA-induced response was comparable to lipopolysaccharide stimulation. In comparison with MPhi, the response was much weaker in TECs. Likewise, the production of TXA2 in response to HA was markedly increased in MPhi, but less in TECs. In TECs and in MPhi, the HA-stimulated TXA2 synthesis was inhibited with the COX-2-selective inhibitors SC58125 (12.5 micromol/L) or celecoxib (0.25 to 5.00 micromol/L). COX-2 mRNA levels were increased in nephritic mice with MRL-Faslpr lupus nephritis and in mice with anti-GBM disease.


CONCLUSIONS
HA is a proinflammatory factor that stimulates COX-2 expression and subsequent TXA2 production. Since HA accumulates markedly in renal injury, we speculate that this matrix molecule could therefore play a significant role in thromboxane-mediated immune events in the kidney.
Sun
L K
LK
Physiological Institute, University of Zürich-Irchel, Zürich, Switzerland.
Beck-Schimmer
B
B
Oertli
B
B
Wüthrich
R P
RP
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D008181:Lupus Nephritis / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000235:genetics
D007527:Isoenzymes; D012333:RNA, Messenger; D013928:Thromboxane A2; D006820:Hyaluronic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase