The Renal Protective Effects Of Rofocoxib On Renal Interstitial Fibrosis

Objective: Renal interstitial fibrosis is the common way to final renal failure. We have already made much progression on the mechism, renal tubular cells play an important role in development of renal fibrosis. Recent studies suggest excessive tubular cells apoptosis lead to tubular cells decrease,tubular atrophy and tubuloinerstitial fibrosis, so it may be prevent interstitial fibrosis by prohibiting tubular cells excessive apoptosis. Cyclooxygenase(COX) is the rate limiting enzyme for prostaglandin synthesis and has 2 isoforms, COX-1 and COX-2, COX-1 catalyzes the production of prostaglandins involves in the maintenance of regular cellular physiology, whereas COX-2 catalyzes the production of prostaglandins involved in inflammatory processes. It is reported that selective COX-2 inhibitor can alleviate the progression of interstitial fibrosis by decreaseing the level of Transforming growth factor-? (TGF-?). Studies suggest that TGF-? can induce tubular cell apoptosis, anti-TGF-?　antibody can alleviate the tubular apoptosis, but weather selective COX-2 inhibitor can affect the level of tubular cell apoptosis is unknown. In this experiment, we observe the effect of seclctive COX-2 inhibitor rofocoxib on the renal tubular cell apoptosis,TGF-??,COX-2 and CollagenⅠ(ColⅠ) in rats with UUO.Methods: 45 Male SD rats were randomly divide into 3 groups: sham-operated group(A group; N=15), UUO group(B group；N=15), UUO treated with rofocoxib group (C group；N=15). Under pentobarbitale sodium anesthesia the rat's left ureter was ligated with 0 silk at two points and cut between the ligatures. Then the unilateral ureteral obstructive rat model was established. A group rats had their ureters manipulated but not ligated. Rofocoxib was administered to rats 1 day before surgery and every day thereafter. Rats were killed after 3,7,14 days. In obstructed kidney, apoptosis was detected by terminal deoxynucleotidy 1 transferasemediated dUTP nick endlabeling assay(TUNEL) .TGF-??,COX-2 and ColⅠwere examined by immunohistochemical staining, Histological changes were observed by HE stain and Masson stain. The urinary concentration of thromboxane B2(TXB2) was determined by radioimmunoassay.Results: There were different degree of interstitial fibrosis, tubular dilation, and the interstitial area expansion in the obstructed kidneys of group B3,7,14 days after UUO. The area of the renal interstitial was significantly increased in the obstructed kidneys compared with that of group A(P<0.01).The renal interstitial area in kidneys of group C significantly decreased compared with that of group B(P<0.01). At every time point, apoptosis cells in renal tubular were significantly increased in B group and reduced by rofocoxib treatment(P<0.01) .By immunohistological staining, The protein level of COX-2,TGF-?? and ColⅠ in B3,B7,B14 groups was various(P<0.01)and significantly higher than that in groupsA3,A7,A14(P<0.01), in groups C3,C7,C14, The protein level of COX-2,TGF-???and ColⅠ was significantly lower than B3,B7,B14 groups(P<0.01). In B group, the urinary concentation of TXB2 increased substantially. In C group, TXB2 concentation apparently lower than B group(P<0.01). Conclusions: COX-2 is involved in the pathogenesis of the injury of UUO, selective COX-2 inhibotor-rofocoxib inhibit COX-2 activity, reduces COX-2 protein expression, reduces TXB2 concentation. Rofocoxib reduces renal tubular cells excessive apoptosis and reduces renal cortices transforming growth factor-?,collagen Ⅰ protein expression, resulting in decreased tubular damage and interstitial fibrosis.