The comparative pathobiology of α2u-globulin nephropathy

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

“…The DAAO accumulation in rat kidney appears similar to the well-described hyaline droplet nephropathy in male rats (Swenberg et al 1989;Dietrich and Rasonyi 1995). This nephropathy is characterized by the renal proximal tubule epithelial accumulation of α2-urinary globulin, a fatty acid-binding protein synthesized exclusively in the liver of male rats and reabsorbed in the renal proximal tubules.…”

“…60 h (Cappelletti et al 2013);α2u-globulin: approx. 6 h (Lehman-McKeeman et al 1990)), whereby binding of chemicals to α2u-globulin extends this half-life markedly and exacerbates the accumulation of α2u-globulin in the lysosomes of exposed male rats (Swenberg et al 1989;Lehman-McKeeman et al 1990;Frazier et al 2012). Consequently, we investigated whether propiverine interacts with DAAO in vitro, thus resulting in the cytosolic and nuclear DAAO accumulations observed in vivo.…”

“…The mechanisms underlying the observed process are so far poorly understood. However, a similar process, the accumulation of α2u-globulin, is a well-described phenomenon in rat kidney that is caused by the reversible binding of chemicals to α2u-globulin resulting in a decreased degradation of the protein (Swenberg et al 1989). Thus, we first evaluated the ability of propiverine or propiverine-N-oxide to interact with recombinant rat DAAO (rDAAO).…”

“…This nephropathy is characterized by the renal proximal tubule epithelial accumulation of α2-urinary globulin, a fatty acid-binding protein synthesized exclusively in the liver of male rats and reabsorbed in the renal proximal tubules. The accumulation of α2u-globulin is governed by the reversible binding of compounds or their metabolites, resulting in slower enzymatic degradation of α2u-globulin (Swenberg et al 1989;Lehman-McKeeman et al 1990;Frazier et al 2012). Of note, the analogous mouse urinary protein (MUP) does not bind the α2u-binding compounds nor does it accumulate in the renal proximal tubules of mice (Dietrich and Rasonyi 1995), reminiscent of the situation described for the species-specific propiverine-induced rDAAO accumulation.…”

Retrospective study of possible alpha-2 mu-globulin nephropathy and associated cell proliferation in male Fischer 344 rats dosed with t-butyl alcohol.

“…The presence of an increase in protein droplets in renal tubular epithelial cells along with the occurrence of abnormally shaped cytoplasmic protein deposits is a hallmark of a-2p-globulin nephropathy (2,3). Since the proposed mechanism by which a-2p-globulin nephropathy leads to an increase in renal tumors supposedly involves cytotoxicity and secondary enhancement of cell proliferation (3)(4)(5)(6), we retrospectively examined kidney sections to determine if there was enhanced replicative DNA synthesis as indicated by the presence of S-phase nuclei.…”