The Effect And Mechanism Of Estrogen On Experimental Tubulointerstitial Fibrosis Rats

Objective: Tubulointerstitial fibrosis (TIF) is a common pathological features of end-stage kidney disease. It has been shown that the decline of renal function correlates better with tubulointerstitial fibrosis than glomerulosclerosis, thus tubulointerstitial fibrosis in progressive renal disease is now believed to be the most reliable marker of disease severity. Accumulating data suggest that estrogen and its metabolites are renoprotective, but its effect on tubulointerstitial fibrosis and the underlying mechanisms are still unclear. In this study, we use a rat model of tubulointerstitial fibrosis, which induced by unilateral ureteral obstruction(UUO), and we make various estrogen level in various groups by ovariectomized or celiac 17β-estradiol implanted, so we examined the effect of estrogen on the morphology and the expressions of TGF-β1,α-SMA and TIMP-1 of obstructie kidneys and the possible mechanism underlying that.Method: Thirty Sprague-Dawley femal rats were randomly divided into four group, control group, low estrogen group(OVX+UUO), normal estrogen group(UUO) and high estrogen group(UUO+17-E2). The low estrogen group were ovariectomized(OVX); the normal and high estrogen group underwent sham operation of OVX. Four weeks later, all groups underwent UUO, except the control group, and the high estrogen group were received 17β-estradiol injection in the same day, the other groups were received sesame oil injection. The rats were killed after 21 days, renal tissues were examined by microscope. Immunohistochemistry was applied to determine the protein expressions of TGF-β1,α-SMA and TIMP-1, the mRNA expressions ofα-SMA and TIMP-1 were detected semiquantitatively with reverse transcription-polymerase chain reaction.Results: (1) PAS and Masson staining of the renal tissue revealed that there appeared inflammatory cell infiltration, renal tubule atrophy and fibrosis in UUO groups. In low estrogen group, the lesion was most evident. As the increase of estrogen level in UUO groups, the lesion was attenuated. Compared with normal estrogen group, tubule interstitial damage index ascended in low estrogen group(p<0.05), while in high estrogen group which descended(p<0.05). (2) Immunohistochemistry showed that in comparison with control group, the protein expression of TGF-β1,α-SMA and TIMP-1 significantly increased in UUO groups. Compared with normal estrogen group, the expression of those enhanced in low estrogen group(all p<0.05), and in high estrogen group the expression of those decreased(all p<0.05). (3) Renal expressions ofα-SMA and TIMP-1 mRNA in UUO groups were significantly increased than in control group; compared with normal estrogen group, the expression of those increased in low estrogen group(all p<0.05), while in high estrogen group the expression of those decreased(all p<0.05).Conclusion: (1) We observed that in rat model of UUO, estrogen improved the histological lesion and prevent the development of tubulointerstitial fibrosis. (2) Estrogen can inhibit the over expression of TGF-β1,α-SMA and TIMP-1, which may consequently result in the sediment of extracellular matrix.(3) Estrogen may prevent the development of interstitial fibrosis by inhibiting over expression of TGF-β1 ,α-SMA and TIMP-1.