TISSUE FACTOR EXPRESSION IN AN ANIMAL-MODEL OF HYDRONEPHROSIS

Background. Hydronephrosis is associated with interstitial fibrosis an d occlusion of renal capillaries by fibrin. However, the mechanisms le ading to fibrin formation is unknown. Methods and results. Twenty days after unilateral ligation of the ureter, interstitial fibrosis occurr ed in the ligated kidney. Fibrosis was preceded by infiltration of inf lammatory cells (macrophages, B and T lymphocytes). Staining with an a ntibody against von Willebrand factor demonstrated newly formed capill aries in the fibrosing tissue as well as prominent fibrin deposition. Fibrin staining was found around vessels, in the interstitium, the glo meruli, and tubuli. Fibrin deposition was less prominent in the non-li gated kidney and almost absent in sham-operated animals. The expressio n of tissue factor, the central initiator of coagulation, was induced within 5 days after ligation in the operated kidney but not in the sha m-operated animals. Tissue factor positivity was observed by immunohis tochemistry in vascular endothelial cells, the vessel wall, tubular ep ithelial cells, glomerular capsular cells, Bowman's space and in the i nterstitium. Tissue factor induction was due to increased transcriptio n, since in-situ hybridization showed increased levels of mRNA in the ligated kidney compared to sham-operated rats. The tissue factor gene is under control of the transcription factors activator protein-1 (AP- 1) and nuclear factor-kB (NF-kB). When extracts of operated organs wer e compared with kidneys of sham-operated rats or contralateral kidneys in electrophoretic mobility shift assays, an increase in AP-1 and NF- kB binding activity to their respective binding sites in the tissue fa ctor gene was observed in the operated, but not in the contralateral k idney or kidneys of sham-operated animals. Conclusion. Ureteral ligati on leads to infiltration of inflammatory cells, increased AP-1 and NF- kB expression in the kidney, resulting in increased tissue factor tran scription and translation, and ultimately in increased fibrin depositi on.