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.
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Notes
http://thebiogrid.org/107980, 20.11.15.
Abbreviations
- Prop.:
-
Propiverine
- rDAAO:
-
Rat d-amino acid oxidase
- hDAAO:
-
Human d-amino acid oxidase
- mDAAO:
-
Mouse d-amino acid oxidase
- CD:
-
Circular dichroism
- BF:
-
Bright field
- ABCD3:
-
ATP-binding cassette subfamily D member
- LAMP2:
-
Lysosomal-associated membrane protein 2
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Acknowledgments
This work was supported by the Deutsche Deutsche Forschungsgemeinschaft, DFG (RTG 1331). LP and SS were supported by Grant from Fondo di Ateneo per la Ricerca. We gratefully acknowledge Apogepha Arzneimittel GmbH (Germany) for supplying propiverine and propiverine-N-oxide. We thank Dr. S. Erath and Prof. Dr. M. Groettrup for providing substances for, and hands-on instructions with, the proteasome activity assay as well as K. Collins and C. Grimm for technical assistance. In addition, we thank the BioImaging Center (BIC, University of Konstanz) for instrumentation.
Author contributions
L. Luks designed and performed most of the experiments, analyzed, interpreted and discussed the evolving data, and wrote the manuscript. S. Sacchi and L. Pollegioni performed the in vitro binding experiments and edited the manuscript. D.R. Dietrich designed the overall research goals and approaches, interpreted and discussed the evolving data, and was deeply involved in manuscript writing. All authors read and approved the final manuscript.
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Suppl. Figure 1
Catalase loses peroxisomal localization after propiverine treatment. Confocal microscopy of kidney sections from male F344 rats after placebo or propiverine treatment. Co-staining of peroxisomal membrane protein ABCD3 and peroxisomal enzyme catalase. A) Catalase is located in peroxisomes in control animals. B) Peroxisomal localization of catalase is partly lost after propiverine treatment. Catalase accumulates in nuclei and cytosol but is also diffusely distributed in the cytosol. Black scale bar: 20 µm, scale bar in magnification box: 5 µm. prop. = propiverine (TIFF 4366 kb)
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Luks, L., Sacchi, S., Pollegioni, L. et al. Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo. Arch Toxicol 91, 427–437 (2017). https://doi.org/10.1007/s00204-016-1685-z
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DOI: https://doi.org/10.1007/s00204-016-1685-z
Keywords
- Propiverine
- d-Amino acid oxidase
- Renal protein accumulation
- Protein mistrafficking