Expression of Mediators of Renal Injury in the Remnant Kidney of ROP Mice Is Attenuated by Cyclooxygenase-2 Inhibition

To investigate the effects of cyclooxygenase-2 (COX-2) inhibition on renal injury of mice, ROP mice were subjected to subtotal ablation (‘remnant’). A subset of the remnant group was treated with a selective COX-2 inhibitor, SC58236, in the drinking water. At 12 weeks the remnant group developed significant albuminuria (181.3 ± 15.8 µg/24 h), which was blunted by SC58236 treatment (138.9 ± 17.1; p < 0.05 compared to remnant). SC58236 did not alter systemic blood pressure or GFR significantly. Immunoreactive COX-2 was upregulated in remnant (1.88 ± 0.35 fold sham, n = 8, p < 0.05), which was blunted by SC58236 (to 1.26 ± 0.31 fold sham). Collagen IV mRNA increased significantly in remnant kidneys (2.69 ± 0.34 fold sham, n = 8, p < 0.05), and this increase was inhibited by SC58236 treatment (to 1.84 ± 0.32 fold control). Immunoreactive TGF-β1, connective tissue growth factor, HGF receptor, c-Met, and fibronectin all increased in remnant (2.85 ± 0.51, 3.83 ± 0.55, 2.56 ± 0.31, and 2.80 ± 0.39 fold sham respectively, n = 4–8, p < 0.05), and SC58236 blunted the increases (to 1.45 ± 0.34, 1.85 ± 0.13, 1.75 ± 0.30, and 1.60 ± 0.32 fold sham). Immunohistochemistry indicated that the major localization for these progression factors was in the tubulointerstitium, especially in the scar area, which is in agreement with the expression of a macrophage marker, F4/80. Therefore, these results indicate that in a mouse model of subtotal renal ablation, COX-2 inhibition blocks expression of mediators of renal tubulointerstitial injury.