Aop: 257

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Angela Mally   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Angela Mally

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.43 Included in OECD Work Plan
This AOP was last modified on June 04, 2021 15:03

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) March 03, 2022 15:14
Occurrence, Kidney toxicity March 04, 2022 10:58
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 March 08, 2022 11:46
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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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]

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1486 Binding of substrate, endocytic receptor Binding of substrate, endocytic receptor
KE 831 Disturbance, Lysosomal function Disturbance, Lysosomal function
KE 898 Disruption, Lysosome Disruption, Lysosome
KE 709 Increase, Cytotoxicity (renal tubular cell) Increase, Cytotoxicity (renal tubular cell)
AO 814 Occurrence, Kidney toxicity Occurrence, Kidney toxicity

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages Not Specified

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
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

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

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

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

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

List of the literature that was cited for this AOP. More help

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.