Prostaglandin E₂ Reduces Obstructive Renal Fibrosis By Promoting Lymphangiogenesis

Objective:To study the effect of PGE₂ on obstructive renal fibrosis and provide a new strategy for the prevention and treatment of obstructive renal fibrosis.Methods:Male C57BL/6 mice at 6-8 weeks were randomly divided into 3 groups according to whether they received unilateral ureteral obstruction operation or not and different postoperative administration,which were Sham operation group（S group）,unilateral ureteral obstruction group（U group）and PGE₂treatment group（P group）.After anesthesia,the left upper ureter was separated from the renal pelvis,and the left ureter was ligated and disconnected in U group and P group,and only the left upper segment of ureter was separated from the renal pelvis of mice in group S,neither ligated nor continuously opened.P group began daily intraperitoneal injection of PGE₂（5mg/kg/day）on the 1st postoperative day,and group S and U was injected with the same dose of NS daily for 14 consecutive days.On day 3,7 and 14 after surgery,6 mice in each group were randomly selected to collect bilateral kidney for observation.All left kidney specimens were stained with HE to observe the histological changes,Masson staining to observe the degree of fibrosis,and IHC to detect the expression ofα-SMA,TGF-β1,LYVE-1,VEGF-C.Results:1.Pathological injury Gross appearance:There was no obvious change in bilateral renal appearance in S group.In U and P groups,left kidney congestion swelling,and with the extension of obstruction time gradually increased.HE staining results:The renal structure of S group was intact and the glomerulus was full.In U group,with the prolongation of obstruction time,the number of interstitial inflammatory cells increased,the glomerulus shrank,the epithelial cells of the renal tubules were degeneration and degeneration,and the renal tubules were deformed and expanded,and the tubular type appeared.However,the changes in P group were lighter and appeared later than those in U group.2.Fibrosis condition Masson staining:In S group,there were only few blue stained collagen fibers around arterioles.The area of interstitial blue staining in U group and P group gradually expanded with the extension of obstruction time,and the area of interstitial blue staining in P group was less than that in U group at the same time point（P<0.05）.Immunohistochemical ofα-SMA:In the S group,only a very low level of expression was found in the cytoplasm of renal tubular epithelial cells.With the prolongation of obstruction time,the strongly positive interstitial regions increased in U group and P group,and the expression of P group was lower than that of U group at the same time point（P<0.05）.Immunohistochemical of TGF-β1:In S group,the expression was only very low in the cytoplasm of renal tubular epithelial cells.The expression of U group and P group increased gradually with the extension of obstruction time,but the expression of P group was significantly less than that of U group at the same time point（P<0.05）.3.lymphangiogenesis condition Immunohistochemical of LYVE-1:The lymphangiogenesis of the S group were rare.The number of lymphangiogenesis in the interstitium of U group and P group was large and showed an increasing trend with the extension of obstruction time.The density of lymphangiogenesis in P group was larger than that in U group at the same time point（P<0.05）.4.VEGF-C expression:In S group,strong expression was occasionally found in renal tubular epithelial cells.The expression level of the U and P groups increased significantly,and the number of renal tubular epithelial cells with strong positive expression gradually increased with the prolongation of obstruction time.The expression level of P group was higher than that of U group at the same time point（P<0.05）.Conclusion:1.After ureteral obstruction,renal fibrosis gradually occurred,and with the extension of obstruction time,the degree of fibrosis continued to aggravate.2.PGE₂alleviates renal injury caused by ureteral obstruction and delays the progression of renal fibrosis,the mechanism of which may be related to the secretion of VEGF-C by renal tubular epithelial cells to promote the lymphangiogenesis.