title: Novel insights into renal D-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo.
abstract: Chronic exposure to propiverine, a frequently prescribed pharmaceutical for treatment of overactive bladder and incontinence, provokes massive protein accumulation in the cytosol and nucleus of renal proximal tubule epithelial cells in rats. Previously, the accumulating protein was identified as D-amino acid oxidase (DAAO), a peroxisomal flavoenzyme expressed in kidney, liver and brain. The cellular mechanism of propiverine-induced DAAO accumulation, however, remains unexplained and poorly characterized. Therefore, to further increase the understanding of DAAO accumulation in rat kidney, this study aimed to characterize DAAO accumulations using differential immunofluorescent staining of rat kidney sections as well as in vitro binding analyses and proteasomal activity studies. We demonstrated that propiverine is neither a ligand of DAAO nor an inhibitor of the proteasome in vitro. However, propiverine treatment resulted in a significant decrease of peroxisomal size in rat proximal tubule epithelial cells. Moreover, peroxisomal catalase also accumulated in the cytosol and nuclei of propiverine-treated rats concurrently with DAAO. Taken together, our study indicates that propiverine treatment affects the trafficking and/or degradation of peroxisomal proteins such as DAAO and catalase by a so far unique and unknown mechanism.
authors.affiliation: Human and Environmental Toxicology, University of Konstanz, Universitätsstrasse 10, 78457, Constance, Germany.
authors.forename: Lisanne
authors.initials: L
authors.lastname: Luks
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.|The Protein Factory Research Center, Politecnico di Milano and University of Insubria, Milan, Varese, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sacchi
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.|The Protein Factory Research Center, Politecnico di Milano and University of Insubria, Milan, Varese, Italy.
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.affiliation: Human and Environmental Toxicology, University of Konstanz, Universitätsstrasse 10, 78457, Constance, Germany. daniel.dietrich@uni-konstanz.de.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D001561:Benzilates / Q000008:administration & dosage / Q000009:adverse effects*; D002374:Catalase / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003605:D-Amino-Acid Oxidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004795:Enzyme Stability / Q000187:drug effects; D005260:Female; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D053141:Organelle Size / Q000187:drug effects; D020675:Peroxisomes / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D036401:Toxicity Tests, Chronic; D064804:Urological Agents / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D001561:Benzilates; D018680:Cholinergic Antagonists; D011994:Recombinant Proteins; D064804:Urological Agents; C015586:propiverine; D002374:Catalase; D003605:D-Amino-Acid Oxidase
keywords: D-Amino acid oxidase; Propiverine; Protein mistrafficking; Renal protein accumulation