Increased Expression of Glomerular von Willebrand Factor after Irradiation of the Mouse Kidney

Abstract

Ionizing irradiation has been shown to induce an increased release of von Willebrand factor (vWF) in human endothelial cells in vitro. The present study was undertaken to investigate whether an increase in expression of vWF also occurs in glomerular endothelial cells in vivo after irradiation of the kidney. Increased expression of vWF may initiate prothrombotic changes, and the resultant vascular damage could cause renal failure. The amount of adherent leukocytes in the renal cortex after irradiation was also quantified, since this may contribute to the histological changes that occur after irradiation. Changes in expression of glomerular vWF and in the amount of leukocytes were related to the development of impairment of renal function, as assessed with the [51Cr]EDTA retention assay. Mice were given bilateral irradiation (single dose of 16 Gy) or were sham-irradiated and were sacrificed at intervals of 1 day to 40 weeks after irradiation. Immunohistochemical analysis of kidney cryosections was performed using a polyclonal vWF antibody or monoclonal CD45 antibody (leukocyte common antigen). The amount of glomerular vWF staining and CD45 staining in the renal cortex (percentage surface coverage) was quantified using a computerized image analyzer. The mean glomerular vWF staining in the nonirradiated kidneys was 34.4 +/- 6.2% (mean +/- SEM, 10 weeks after sham treatment). After irradiation, the expression of glomerular vWF increased gradually from 10 weeks to 53.4 +/- 3.6% at 40 weeks. The total number of leukocytes in the renal cortex of nonirradiated mice at 10 weeks after sham treatment was low, with a mean area of 1.0 +/- 0.09%, whereas in the irradiated kidneys the relative tissue area covered by leukocytes increased to 7.6 +/- 2.1% at 40 weeks. These alterations preceded impairment of renal function. The extent to which these changes are causally related to impairment of function will be the subject of future study using specific antithrombotic and anti-inflammatory agents.