BACKGROUND: Hydronephrosis is associated with interstitial fibrosis and occlusion of renal capillaries by fibrin. However, the mechanisms leading to fibrin formation is unknown. METHODS AND RESULTS: Twenty days after unilateral ligation of the ureter, interstitial fibrosis occurred in the ligated kidney. Fibrosis was preceded by infiltration of inflammatory cells (macrophages, B and T lymphocytes). Staining with an antibody against von Willebrand factor demonstrated newly formed capillaries in the fibrosing tissue as well as prominent fibrin deposition. Fibrin staining was found around vessels, in the interstitium, the glomeruli, and tubuli. Fibrin deposition was less prominent in the non-ligated kidney and almost absent in sham-operated animals. The expression of tissue factor, the central initiator of coagulation, was induced within 5 days after ligation in the operated kidney but not in the sham-operated animals. Tissue factor positivity was observed by immunohistochemistry in vascular endothelial cells, the vessel wall, tubular epithelial cells, glomerular capsular cells, Bowman's space and in the interstitium. Tissue factor induction was due to increased transcription, 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-kappa B (NF-kappa B). When extracts of operated organs were compared with kidneys of sham-operated rats or contralateral kidneys in electrophoretic mobility shift assays, an increase in AP-1 and NF-kappa B binding activity to their respective binding sites in the tissue factor gene was observed in the operated, but not in the contralateral kidney or kidneys of sham-operated animals. CONCLUSION: Ureteral ligation leads to infiltration of inflammatory cells, increased AP-1 and NF-kappa B expression in the kidney, resulting in increased tissue factor transcription and translation, and ultimately in increased fibrin deposition.
BACKGROUND:Hydronephrosis is associated with interstitial fibrosis and occlusion of renal capillaries by fibrin. However, the mechanisms leading to fibrin formation is unknown. METHODS AND RESULTS: Twenty days after unilateral ligation of the ureter, interstitial fibrosis occurred in the ligated kidney. Fibrosis was preceded by infiltration of inflammatory cells (macrophages, B and T lymphocytes). Staining with an antibody against von Willebrand factor demonstrated newly formed capillaries in the fibrosing tissue as well as prominent fibrin deposition. Fibrin staining was found around vessels, in the interstitium, the glomeruli, and tubuli. Fibrin deposition was less prominent in the non-ligated kidney and almost absent in sham-operated animals. The expression of tissue factor, the central initiator of coagulation, was induced within 5 days after ligation in the operated kidney but not in the sham-operated animals. Tissue factor positivity was observed by immunohistochemistry in vascular endothelial cells, the vessel wall, tubular epithelial cells, glomerular capsular cells, Bowman's space and in the interstitium. Tissue factor induction was due to increased transcription, 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-kappa B (NF-kappa B). When extracts of operated organs were compared with kidneys of sham-operated rats or contralateral kidneys in electrophoretic mobility shift assays, an increase in AP-1 and NF-kappa B binding activity to their respective binding sites in the tissue factor gene was observed in the operated, but not in the contralateral kidney or kidneys of sham-operated animals. CONCLUSION: Ureteral ligation leads to infiltration of inflammatory cells, increased AP-1 and NF-kappa B expression in the kidney, resulting in increased tissue factor transcription and translation, and ultimately in increased fibrin deposition.