| Objective: To investigate the preventive effects of piperazine ferulate ( a new type nonpeptide endothelin receptor antagonist ) on the progression of renal interstitial fibrosis following unilateral ureteral obstruction(UUO) and mechanism. Methods: Seventy-five male, Sprague-Dauley ( SD ) rats, clean animal grade, were randomly divided into the following 5 groups: Sham group, UUO group, PF Group ( piperazine ferulate treatment group ), ACEI group ( enalapril treatment group ), PF+ACEI group ( piperazine ferulate and enalapril treatment group ), and were obstructed left ureter through an abdominal incision under sterile conditions. In Sham group, left ureters were separated, but weren't obstructed and the rest procedures were the same. Piperazine ferulate (50mg/Kg/d), enalapril (10mg/Kg/d), piperazine ferulate (50mg/Kg/d)+enalapril (10mg/Kg/d) which were dissolved in normal saline were separately administered by gavage once a day from two days before operations. Rats of UUO group and Sham group were administered by gavage by normal saline of equal volume. On the 3th day, 7th day and 14th day after operation, rats were sacrificed by exsanguinations. Left renals were removed and weighted by electric scales. The rates of renal weight and body weight were counted. The contents of hydroxyproline were measured, and the rates of collagen and renal weight were counted. ( Total collagen contains 12.7% hydroxyproline, and other proteins don't contain or contain few hydroxyproline.) The expression of transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF), bone morphogenetic protein-7 (BMP-7) and CD34 were measured by immunohistochemistry, then calculated the positive area ratio by the pathologic picture analysis. Regarding CD34 as the symbol of peritubular capillary and counting the peritubular capillary index ( PCI ). Results: ①The changes of pathology and collagen: After UUO, there were obstructed renal swelling, pyelocaliectasis, loss of parenchyma of renal and the renal weight decreasing. From the 7th day, the rates of renal weight and body weight of UUO group had statistical significance compared with Sham group, p<0.05. But on the 14th day, all treatment groups had statistical significance compared with Sham group, p<0.05, and had no obviously distinct compared with UUO group. In microscope, there were tubule dilation, tubule atrophy and monocytes infiltration in renal interstitium. The interstitial fibrosis was turning up gradually from cortex-medulla junction, but there were no pathological changes in glomeruli. After UUO, collagen of renal tissue of UUO group and all treatment groupswere increasing gradually, and had statistical significance compared with Sham group, p<0.05. All treatment groups inhibited the increases of collagen. From the 7th day, there was statistical significance between PF+ACEI group and UUO group, but PF group and ACEI group had statistical significance compared with UUO group on the 14th day, p<0.05.②The expression of co-fibrosis factors(TGF-β1,TIMP-1): From the 3th day after UUO, the positive area of TGF-β1 of UUO group and PF group increased and had statistical significance compared with Sham group. The area of ACEI group and PF+ACEI group had statistical significance compared with Sham group from the 7th day, p<0.05. From the 7th day, there was statistical significance between all treatment groups and UUO group, p<0.05. On the 14th the day, the effects of ACEI group and PF+ACEI group were maintained, but there was no obviously distinct between PF group and UUO group, p>0.05. The area of TGF-β1 had a significant positive correlation with the collagen, r=0.663 , p < 0.001. From the 3th day, the expression of TIMP-1 of UUO group and all treatment groups increased and had statistical significance compared with Sham group. The inhibited role of enalapril and combined drugs were more early and there was statistical significance between them and UUO group on the 3th day, but on the 7th day, PF group had statist... |
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