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Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of mitochondrial DNA polymerase gamma leading to kidney toxicity||adjacent||High||Moderate||Angela Mally (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity||adjacent||High||Moderate||Angela Mally (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Renal protein alkylation leading to kidney toxicity||adjacent||High||Moderate||Angela Mally (send email)||Not under active development||Under Development|
|Inhibition of mitochondrial electron transport chain (ETC) complexes leading to kidney toxicity||adjacent||Not Specified||Not Specified||Baki Sadi (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Excessive renal tubular cytotoxicity, both apoptotic and necrotic, leads to the eventual failure of the kidneys (Priante et al., 2019). This is because the mass cytotoxicity of renal tubular cells leads to the inability of the nephrons to properly filter nutrients and waste from the blood (Pirante et al., 2019). The kidneys can make compensational adjustments to the nephrons to continue adequate filtration up to the loss of 75% of the nephrons, beyond this amount of nephron loss, the kidneys lose function (Orr and Bridges, 2017).
Evidence Collection Strategy
Evidence Supporting this KER
Renal tubular cells are very important functional units of the nephrons (Priante et al., 2019). The tubular cells are essential for the proper removal of waste material from the blood, as well as retaining essential nutrients, water, and salt levels for homeostatic blood content (Priante et al., 2019). The S3 segment of the proximal tubule in particular is highly susceptible to damage by environmental toxicants (Lentini et al., 2017). Apoptosis is the preferred method of cell death for renal tubule cells, as injured cells need to be removed without inducing an inflammatory response (Priante et al., 2019). By forming apoptotic bodies that can be recycled via phagocytes or epithelial cells, the kidney avoids the induction of an inflammatory response which causes the injury of surrounding, healthy cells. However, when apoptotic bodies are not phagocytosed quickly enough, their membranes can become damaged. This causes the apoptotic bodies to enter secondary necrosis, lysing and releasing their contents to the extracellular space. The immune cells will instigate an inflammatory response as a result, causing the injury to nearby tubular cells through the release of granule contents of by the immune cells (Priante et al., 2019). Remarkably, thanks to compensatory functional, molecular, and structural changes in the kidney, the remaining healthy nephrons are able to function adequately until more than 75% of them die (Orr and Bridges, 2017). After the loss of more than 75% of the nephrons however the remaining nephrons are no longer able to effectively remove environmental toxicants or waste from the filtrate, resulting in failed renal function (Orr and Bridges, 2017).
Uncertainties and Inconsistencies
There are no currently known inconsistencies or uncertainties for this relationship.
Known modulating factors
There are several known modulating factors of the relationship between renal tubular cytotoxicity and kidney failure. One modulator of this relationship is age.
There is a defined response-response relationship for renal tubule cytotoxicity leading to kidney failure. The loss of 75% of the nephrons to damage is the threshold for kidney failure (Orr and Bridges, 2017). This is due to the ability of the kidneys to make changes in the structure and function of the remaining nephrons at a molecular level to compensate for the lost nephrons (Orr and Bridges, 2017). The kidneys are able to retain adequate functioning until only 25% of the original nephrons remain, at which point the compensatory changes cannot maintain kidney functioning and kidney failure is final (Orr and Bridges, 2017).
Known Feedforward/Feedback loops influencing this KER
There are no known feedforward/feedback loops that influence this relationship.
Domain of Applicability
The domain of applicability only includes vertebrates, as invertebrates and non-animals do not have kidneys (Mahasen, 2016).
Lentini, P., Zanoli, L., Granata, A., Signorelli, S. S., Castellino, P., & Dell'aquila, R. (2017).
Kidney and heavy metals - the role of environmental exposure (review). Molecular Medicine Reports, 15(3413), 3419. doi:10.3892/mmr.2017.6389
Mahasen, L. M. A. (2016). Evolution of the kidney. Anatomy Physiol. Biochem. Int. J., 1(1),
Orr, S. E., & Bridges, C. C. (2017). Chronic kidney disease and exposure to nephrotoxic
metals. International Journal of Molecular Sciences, 18 doi:10.3390/ijms18051039
Priante, G., Gianesello, L., Ceol, M., Del Prete, D., & Anglani, F. (2019). Cell death in the
kidney. International Journal of Molecular Sciences, 20(14), 3598. doi: 10.3390/ijms20143598. doi:10.3390/ijms20143598
Sano, K., Fujigaki, Y., Miyaji, T., Ikegaya, N., Ohishi, K., Yonemura, K., & Hishida, A. (2000).
Role of apoptosis in uranyl acetate-induced acute renal failure and acquired resistance to uranyl acetate. Kidney International, 57(4), 1560-1570. doi:10.1046/j.1523-1755.2000.00777.x