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Aop: 257

AOP Title

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Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity

Short name:

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Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity

Graphical Representation

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Click to download graphical representation template

Authors

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Prof. Dr. Angela Mally
Department of Toxicology
University of Würzburg
Versbacher Str. 9
97078 Würzburg
Germany
Phone: +49 931 31-81194
Email: mally@toxi.uni-wuerzburg.de (mailto:mally@toxi.uni-wuerzburg.de)
 

Point of Contact

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Angela Mally   (email point of contact)

Contributors

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  • Angela Mally

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on October 25, 2017 08:56

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Revision dates for related pages

Page Revision Date/Time
Binding of substrate, endocytic receptor October 25, 2017 08:49
Disturbance, Lysosomal function September 16, 2017 10:16
Disruption, Lysosome November 12, 2018 08:23
Increase, Cytotoxicity (renal tubular cell) September 16, 2017 10:16
Occurrence, Kidney toxicity September 16, 2017 10:16
Binding of substrate, endocytic receptor leads to Disturbance, Lysosomal function October 25, 2017 08:46
Disturbance, Lysosomal function leads to Disruption, Lysosome October 25, 2017 08:47
Disruption, Lysosome leads to Increase, Cytotoxicity (renal tubular cell) October 25, 2017 08:47
Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity October 25, 2017 07:54
Aminoglycosides October 25, 2017 08:29
Gentamicin October 25, 2017 08:30
Tobramycin October 25, 2017 08:30
Vancomycin October 25, 2017 08:31
Polymyxin B October 25, 2017 08:31
Colistin October 25, 2017 08:31
Albumin October 25, 2017 08:32
low molecular weight proteins October 25, 2017 08:32
Cadmium October 25, 2017 08:33

Abstract

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This Adverse Outcome Pathway describes the sequential key events that link lysosomal overload to kidney toxicity. It is well established that polybasic drugs and compounds with peptidic structure (e.g. aminoglycosides, polymyxins), heavy metals bound to proteins (e.g. Cd-metallothionine) and urinary proteins that pass the glomerular filter may bind to multiligand, endocytic receptors expressed at the brush-boarder of renal tubule cells located within the proximal convoluted tubule (PCT), resulting in proximal tubule cell uptake via receptor-mediated endocytosis (MIE) [1-5]. Due to low lysosomal pH, endocytosed compounds may be trapped within lysosomes and accumulate in this organelle, leading to disruption of lysosomal function (KE1) and lysosomal swelling.  Disturbance of lysosomal function eventually leads to disruption of lysosomes (KE2) and release of reactive oxygen species and cytotoxic lysosomal enzymes, resulting in proximal tubule cell toxicity (KE3) [3, 4, 6]


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1486 Binding of substrate, endocytic receptor Binding of substrate, endocytic receptor
2 KE 831 Disturbance, Lysosomal function Disturbance, Lysosomal function
3 KE 898 Disruption, Lysosome Disruption, Lysosome
4 KE 709 Increase, Cytotoxicity (renal tubular cell) Increase, Cytotoxicity (renal tubular cell)
5 AO 814 Occurrence, Kidney toxicity Occurrence, Kidney toxicity

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Binding of substrate, endocytic receptor leads to Disturbance, Lysosomal function adjacent High Low
Disturbance, Lysosomal function leads to Disruption, Lysosome adjacent High Low
Disruption, Lysosome leads to Increase, Cytotoxicity (renal tubular cell) adjacent High Low
Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity adjacent High Moderate

Network View

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Stressors

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Name Evidence Term
Aminoglycosides High
Gentamicin High
Tobramycin High
Vancomycin Moderate
Polymyxin B High
Colistin High
Albumin High
low molecular weight proteins High
Cadmium High

Life Stage Applicability

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Life stage Evidence
All life stages Not Specified

Taxonomic Applicability

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Term Scientific Term Evidence Link
Human, rat, mouse Human, rat, mouse High NCBI
dog Canis lupus familiaris Not Specified NCBI
Monkey Monkey Not Specified NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Overall Assessment of the AOP

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Domain of Applicability

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Although mechanistic data on KEs and KERs in this AOP are mostly derived from studies in rodents, the described AOP presents a general mechanism leading to kidney toxicity in wide range of species, including human, mice, rat, dog, monkey.  The described AOP is not limited to a specific life stage or sex.

Human, Mice, Rat, Dog, Monkey


Essentiality of the Key Events

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Evidence Assessment

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Concordance of dose-response relationships

This is still a qualitiative description of the pathway. There is at present no quantitative information on dose-response relationships. Experiments are underway to provide quantitative understanding of dose-response relationships and response-response relationships between upstream and downstream KEs.

 

Temporal concordance among the key events and adverse outcome

The individual KEs are shown to occur prior to or concomitant with the onset of nephrotoxicity.

 

Strength, consistency, and specificity of association of adverse outcome and initiating event

The scientific evidence on the association between inhibition of lysosomal overload initiated by receptor-mediated endocytosis and kidney toxicity (AO) is strong and consistent.

 

Biological plausibility, coherence, and consistency of the experimental evidence

The described AOP is biologically plausible, coherent and supported by experimental data.

 

Alternative mechanism(s) that logically present themselves and the extent to which they may distract from the postulated AOP

There are no alternative mechanism(s) that logically present themselves.

 

Uncertainties, inconsistencies and data gaps

This AOP is plausible and consistent with general biological knowledge. Quantitative information on dose response-relationships as well as response-response relationships for upstream and downstream KEs is needed to support its applicability for the development of alternative in vitro tests for nephrotoxicity testing.


Quantitative Understanding

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Quantitative data on KERs between upstream and downstream KE are still lacking.


Considerations for Potential Applications of the AOP (optional)

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The described AOP is intended to provide a mechanistic framework for the development of in vitro bioactivity assays capable of predicting quantitative points of departure for safety assessment with regard to nephrotoxicity. Such assays may form part of an integrated testing strategy to reduce the need for repeated dose toxicity studies (e.g.  OECD Guideline 407; OECD Guideline 407).


References

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1.           Verroust, P.J., et al., The tandem endocytic receptors megalin and cubilin are important proteins in renal pathology. Kidney Int, 2002. 62(3): p. 745-56.

2.           Moestrup, S.K., et al., Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest, 1995. 96(3): p. 1404-13.

3.           Schnellmann, R.G., Toxic Responses of the Kidney, in Casarett and Doull´s Toxicology. The Basic Science of Poisons, C.D. Klaassen, Editor. 2013, Mcgraw-Hill Education Ltd: Kansas City.

4.           Khan, K.N.M. and C.L. Alden, Kidney, in Handbook of Toxicologic Pathology, W.M. Haschek, C.G. Rousseaux, and M.A. Wallig, Editors. 2002, Academic Press: San Diego.

5.           Thevenod, F., Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol, 2003. 93(4): p. p87-93.

6.           Liu, W.J., et al., Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells. Am J Physiol Renal Physiol, 2015. 308(6): p. F639-49.