Journal
KIDNEY INTERNATIONAL
Volume 59, Issue 1, Pages 190-196Publisher
BLACKWELL SCIENCE INC
DOI: 10.1046/j.1523-1755.2001.00479.x
Keywords
prostaglandins; lupus nephritis; anti-GBM disease; renal injury; inflammation; matrix molecule
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Background. Matrix degradation products such as fragmented hyaluronan (HA) display important proinflammatory effects on renal tubular epithelial cells (TECs) and macrophages (M Phis). We hypothesized that HA could up-regulate cyclooxygenase type 2 (COX-2) in these cells and that the subsequent production of thromboxane A(2) (TXA(2)) could play a role in inflammatory renal lesions. Methods. We used an in vitro approach tb examine the expression of COX-1 and COX-2 and the production of TXA(2) in response to fragments of HA. COX-2 mRNA, protein, and the resulting TXA(2) production were measured in CD44-positive, HA-responsive cells lines of TECs and M Phi. COX-2 mRNA was also measured in vivo in MRL-Fas(lpr) mice and in mice with anti-glomerular basement membrane (anti-GBM) nephritis. Results. In TECs and M Phis, 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 M Phi, the response was much weaker in TECs. Likewise, the production of TXA(2) in response to HA was markedly increased in M Phi, but less in TECs. In TECs and in M Phi, the HA-stimulated TXA(2) synthesis was inhibited with the COX-2-selective inhibitors SC58125 (12.5 mu mol/L) or celecoxib (0.25 to 5.00 mu mol/L). COX-2 mRNA levels were increased in nephritic mice with MRL-Fas(lpr) lupus nephritis and in mice with anti-GEM disease. Conclusions. HA is a proinflammatory factor that stimulates COX-2 expression and subsequent TXA(2) 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.
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