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 microg/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-beta1, 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.
Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tenn 37232-2372, USA. Huifang.Cheng@vanderbilt.edu
Huifang
H
Cheng
Mingzhi
M
Zhang
Gilbert W
GW
Moeckel
Yan
Y
Zhao
Suwan
S
Wang
ZhongHua
Z
Qi
Matthew D
MD
Breyer
Raymond C
RC
Harris
D000818:Animals; D055513:Connective Tissue Growth Factor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005353:Fibronectins / Q000037:antagonists & inhibitors*; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors*; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009392:Nephrectomy; D011507:Proteinuria / Q000503:physiopathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014018:Tissue Distribution; D000096926:Benzenesulfonamides
D055513:Connective Tissue Growth Factor; D052246:Cyclooxygenase 2 Inhibitors; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D019859:Proto-Oncogene Proteins c-met; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C526318:CCN2 protein, mouse