Hyaluronan induced cyclooxygenase-2 expression promotes thromboxane A(2) 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 (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.