Occurrence and cellular localization of PrPd in kidneys of scrapie-affected sheep in the absence of inflammation.

Following a preliminary description of disease-associated prion protein (PrPd) deposition in the kidneys of scrapie-affected sheep, detailed studies have been undertaken in order to evaluate the factors that could account for such PrPd accumulation and to determine the precise location of PrPd in the renal papillae. Immunohistochemical (IHC) examinations for PrPd were conducted in kidneys collected at post-mortem from 30 naturally and 37 experimentally infected sheep. In addition, PrPd detection by western blot analysis (WB) and ultrastructural examination was carried out in a selection of kidneys. PrPd-specific, multifocal IHC labelling with antibody R145 was achieved in the kidneys of 44% and 51% of the naturally and experimentally infected sheep, respectively. The specificity of these results was confirmed by further IHC and WB using several PrP antibodies raised to different amino acid sequences, and by examination of control tissues. PrPd was shown to accumulate in the interstitium of the renal papillae, in association with the cell membrane and lysosomes of fibroblast-like cells, or extracellularly, in close contact with collagen and basal membranes. These deposits were unrelated to inflammatory changes in the kidney as shown by routine histology and by IHC for different immune cell markers. PrPd accumulated in the kidney of sheep that showed widespread PrPd deposition in the lymphoreticular system and had long incubation periods; these findings argue for a haematogenous origin of renal PrPd, although the precise site and mechanism-glomerular filtration and reabsorption at Henle's loop, or extravasation from vasa recta capillaries, or both-by which PrPd leaves the blood to accumulate in the interstitium of renal papillae remain to be determined. Either of these pathogenetic mechanisms could lead to environmental contamination via urine. Crown copyright (c) 2008. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.