Occurrence and cellular localization of Prp(d) in kidneys of scrapie-affected sheep in the absence of inflammation

Following a preliminary description of disease-associated prion protein (PrP(d)) deposition in the kidneys of scrapie-affected sheep, detailed studies have been undertaken in order to evaluate the factors that could account for such Prp(d) accumulation and to determine the precise location of PrP(d) in the renal papillae. Immunohistochemical (IHC) examinations for PrP(d) were conducted in kidneys collected at post-mortem from 30 naturally and 37 experimentally infected sheep. In addition, PrP(d) detection by western blot analysis (WB) and ultrastructural examination was carried out in a selection of kidneys. Prp(d)-specific, multifocal IHC labelling with antibody 8145 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. PrP(d) 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. PrP(d) accumulated in the kidney of sheep that showed widespread PrP(d) deposition in the lymphoreticular system and had long incubation periods; these findings argue for a haematogenous origin of renal PrP(d), although the precise site and mechanism-glomerular filtration and reabsorption at Henle's loop, or extravasation from vasa recta capillaries, or both-by which PrP(d) 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. (C) Crown copyright 2008. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.