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

Luks, Lisanne; Sacchi, Silvia; Pollegioni, Loredano; Dietrich, Daniel R.

doi:10.1007/s00204-016-1685-z

Cited by 9 publications

(22 citation statements)

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“…Since the nucleus represents a major quality control compartment in which misfolded proteins are degraded, impaired degradation can result in protein accumulation (Latonen 2011). As we have recently demonstrated that propiverine does not affect proteasomal activity in vitro (Luks et al 2017), the observed nuclear and cytosolic DAAO accumulation in rat kidneys is unlikely due to an impaired proteasomal degradation. Thus, we hypothesized that altered intracellular trafficking could induce a shift from peroxisomal to nuclear transport of DAAO via two possible mechanisms: (a) Interference with peroxisomal trafficking: DAAO harbors the peroxisomal targeting signal type 1 (PTS1) defined by the C-terminal conserved tripeptide Ser-His-Leu (SHL) (Gould et al 1988).…”

Section: Introductionmentioning

confidence: 48%

“…Since nuclear DAAO accumulation in vivo is accompanied by a complete loss of peroxisomal DAAO (Luks et al 2017), interference with the peroxisomal trafficking machinery (e.g., PEX5) may lead to a shift from peroxisomal to nuclear import. (b) Activation of a putative nuclear import signal: Despite the fact that DAAO has no canonical nuclear localization signal (NLS), we identified a putative nuclear translocation signal (NTS).…”

Section: Introductionmentioning

confidence: 99%

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Understanding renal nuclear protein accumulation: an in vitro approach to explain an in vivo phenomenon

et al. 2017

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Proper subcellular trafficking is essential to prevent protein mislocalization and aggregation. Transport of the peroxisomal enzyme D-amino acid oxidase (DAAO) appears dysregulated by specific pharmaceuticals, e.g., the anti-overactive bladder drug propiverine or a norepinephrine/serotonin reuptake inhibitor (NSRI), resulting in massive cytosolic and nuclear accumulations in rat kidney. To assess the underlying molecular mechanism of the latter, we aimed to characterize the nature of peroxisomal and cyto-nuclear shuttling of human and rat DAAO overexpressed in three cell lines using confocal microscopy. Indeed, interference with peroxisomal transport via deletion of the PTS1 signal or PEX5 knockdown resulted in induced nuclear DAAO localization. Having demonstrated the absence of active nuclear import and employing variably sized mCherry- and/or EYFP-fusion proteins of DAAO and catalase, we showed that peroxisomal proteins ≤134 kDa can passively diffuse into mammalian cell nuclei-thereby contradicting the often-cited 40 kDa diffusion limit. Moreover, their inherent nuclear presence and nuclear accumulation subsequent to proteasome inhibition or abrogated peroxisomal transport suggests that nuclear localization is a characteristic in the lifecycle of peroxisomal proteins. Based on this molecular trafficking analysis, we suggest that pharmaceuticals like propiverine or an NSRI may interfere with peroxisomal protein targeting and import, consequently resulting in massive nuclear protein accumulation in vivo.

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Section: Introductionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Understanding renal nuclear protein accumulation: an in vitro approach to explain an in vivo phenomenon

et al. 2017

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“…Peroxisomal localization of all tested proteins was confirmed using costaining with PMP70, a peroxisomal membrane protein (data not shown). Note that, cytosolic and nuclear protein accumulations in propiverine-exposed rat kidney tissue are visible in bright field images without immunohistochemical staining [11] and were used to localize fluorescent-labeled accumulations in matters of co-localization. Cytosolic and nuclear accumulations are indicated by white arrows and displacement of chromatin, respectively.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…To determine the peroxisome number per visual field (VS), PMP70 positive particles were quantified as described in Ref. [11] using (Fiji Is just) ImageJ software. Briefly, Otsu's method was used for automated clustering-based image thresholding, with a subsequent background filling of particles and watershed-segmentation.…”

Section: Data Handling and Statistical Analysesmentioning

confidence: 99%

“…Since no direct interaction of propiverine or its major metabolite, propiverine-N-oxide, with DAAO was observed, yet a complete loss of DAAO's peroxisomal localization was reported in previous studies [11], the question was raised whether propiverine interferes with the correct protein folding, shuttling and/or import of DAAO into peroxisomes. Indeed, recent in vitro analyses of cyto-nuclear shuttling of human and rat DAAO demonstrated that interference with the peroxisomal transport, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Identification of d -amino acid oxidase and propiverine interaction partners and their potential role in the propiverine-mediated nephropathy

Maier

Luks

Baudendistel

et al. 2018

Chemico-Biological Interactions

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Propiverine, a frequently-prescribed pharmaceutical for the treatment of symptoms associated with overactive bladder syndrome, provoked massive intranuclear and cytosolic protein inclusions in rat proximal tubule epithelium, primarily consisting of the peroxisomal targeting signal 1 (PTS1) containing protein d-amino acid oxidase (DAAO). As this type of nephropathy was also observed for other drugs, the aim was to determine whether propiverine interferes with trafficking and/or import of peroxisomal proteins. To elucidate this, DAAO- and propiverine-specific interaction partners from human HEK293 and rat WKPT cell lines and rat kidney and liver homogenate were determined using co-immunoprecipitation with subsequent nano-ESI-LC-MS/MS analyses. Corroboration of the role of DAAO- and/or propiverine-specific interaction partners in the drug-induced DAAO accumulation was sought via specific immunofluorescence staining of rat kidney sections from control and propiverine-treated rats. Above analyses demonstrated the interaction of propiverine with several protein classes, foremost peroxisomal proteins (DAAO, MFE2, HAOX2) and proteins of the protein quality control system, i.e. chaperones (HSP70 and DnaJ co-chaperones), proteases and proteasomal proteins (regulatory subunits of the 26S proteasome; Rpn1/2). The immunofluorescence analysis revealed mislocalization of many PTS1-proteins (DAAO, CAT, MFE2, ACOX1, EHHADH) in rat renal sections, strongly suggesting that propiverine primarily binds to PTS1 proteins resulting in the formation of PTS1 but not PTS2 or peroxisomal membrane protein (PMP) accumulations. Moreover, chaperones involved in peroxisomal trafficking (HSC70, DnaJB1) and peroxisomal biogenesis factor proteins (PEX3, PEX5, PEX7), also presented with distinct mislocalization patterns. Concomitantly, an increased number of peroxisomes was observed, suggestive of a compensatory mechanism for the presumably suboptimally functioning peroxisomes. Overall, the data presented suggested that propiverine interacts exclusively with DAAO or with a selected number of PTS1 proteins. The consequence of this interaction is the abrogated trafficking and peroxisomal import of PTS1 proteins concomitant with their nuclear and cytosolic accumulation due to inhibited degradation and imbalanced protein homeostasis.

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Protective effect of d-alanine against acute kidney injury

Iwata

Nakade

Kitajima

et al. 2022

American Journal of Physiology-Renal Physiology

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Background. Recent studies revealed the connection between amino acid chirality and diseases. We previously reported that the gut microbiota produced various D-amino acids in a murine acute kidney injury (AKI) model. Here, we further explore the pathophysiological role of D-Alanine (Ala) in AKI. Methods. We analyzed the transcripts of the N-methyl-D-aspartate (NMDA) receptor, a receptor for D-Ala, in tubular epithelial cells (TECs). Then, the therapeutic effect of D-Ala was assessed in vivo and in vitro. Lastly, the plasma level of D-Ala was evaluated in AKI patients. Results. The Grin genes encoding NMDA receptor subtypes were expressed in TECs. Hypoxia condition changes the gene expressions of Grin1, Grin2A and Grin2B. D-Ala protected TECs from hypoxia-related cell injury and induced proliferation after hypoxia. These protective effects are associated with the chirality of D-Ala. D-Ala inhibits ROS production and improves mitochondrial membrane potential, through NMDA receptor signaling. The ratio of D-Ala/L-Ala was increased in feces, plasma, and urine after the induction of I/R. Moreover, enterobacteriaceae, such as Escherichia coli, Klebsiella oxytoca produced D-Ala. The oral administration of D-Ala ameliorated kidney injury after I/R induction in mice. The deficiency of NMDA subunit NR1 on tubular cell worsened kidney damage in AKI. In addition, the plasma level of D-Ala was increased and reflected the level of renal function in AKI patients. Conclusions. D-Ala has protective effects on I/R-induced kidney injury. Moreover, the plasma level of D-Ala reflects the eGFR in AKI patients. D-Ala could be a promising therapeutic target and potential biomarker for AKI.

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

Abstract: propiverine treatment affects the trafficking and/or degradation of peroxisomal proteins such as DAAO and catalase by a so far unique and unknown mechanism.

Cited by 9 publications

References 62 publications

Understanding renal nuclear protein accumulation: an in vitro approach to explain an in vivo phenomenon

Understanding renal nuclear protein accumulation: an in vitro approach to explain an in vivo phenomenon

Identification of d -amino acid oxidase and propiverine interaction partners and their potential role in the propiverine-mediated nephropathy

Protective effect of d-alanine against acute kidney injury

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