This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity
- Angela Mally
|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 Do not cite||Under Development||1.43||Included in OECD Work Plan|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 October 12, 2020 12:40
|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|
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]
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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)
|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|
Life Stage Applicability
|All life stages||Not Specified|
Overall Assessment of the AOP
Domain of Applicability
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
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 data on KERs between upstream and downstream KE are still lacking.
Considerations for Potential Applications of the AOP (optional)
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).
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.