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Relationship: 3253

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, Endothelin protein leads to Increased, afferent artery vasoconstriction

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, Endothelin protein

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, afferent artery vasoconstriction

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Activation of Protein kinase C leads to Kidney Failure	adjacent	High	Moderate	Arthur Author (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The described Key Event Relationship (KER) outlines a sequence of two events related to endothelin and vasoconstriction. The upstream event is characterized by “Increased, endothelin” which refers to the increased production or upregulation of endothelin. Endothelin, a peptide, is a potent vasoconstrictor regulating blood pressure. Endothelin is produced by endothelial and vascular smooth muscle cells (Kawanabe, 2011). Endothelin release is highest in the kidneys compared to other organs. ET-1 is the most relevant isoform of endothelin which exerts its activity on two different receptors including ET_A and ET_B. ET_Ais expressed in vascular smooth muscle cells and ET_Bis expressed in both vascular smooth muscle cells and endothelial cells (Guan, 2015).

The downstream event in this KER is an “Increase, afferent artery vasoconstriction.” Since endothelin is such a potent vasoconstrictor it causes afferent arteries located within the kidney to constrict.

The KER highlights the influence that upregulating or increasing endothelin has on afferent arterioles within the kidney namely vasoconstriction which contributes to various pathophysiological and adverse outcomes.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility of the KER is supported not only be physiological/biological mechanisms but also experimental evidence. It is well established that endothelin is a potent vasoconstrictor, produced namely by endothelial cells. Although there are two different endothelin receptors, one of them is predominantly found on vascular smooth muscle cells which are found in the afferent arterioles of the kidneys. Therefore, the endothelin binds to the receptors in the vascular smooth muscle cells located within the afferent arteries. This ultimately causes the contraction of the smooth muscle cells, therefore vasoconstriction (Guan, 2017).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

1. Dose concordance: Using an in-vitro model of a blood perfused juxtamedullary nephron the renalmicrovascular reactivity was assessed while maintaining the interactions between the renal tubular and vascular. Endothelin causes/has a concentration dependent effect on the vasoconstriction of the afferent arterioles. Despite the concentration dependence, this does not prove dose concordance.

Therefore, to prove dose concordance varying doses of drug stimulating the AOP would need to be used on the above mentioned in-vitro model and then measurements of the increased endothelin and increased afferent arteriole vasoconstriction would need to be taken. Endothelin could be measured using enzyme-linked immunosorbent assay (ELISA). The result would ideally show that increased endothelin occurs at lower or the same dose that increased afferent arteriole vasoconstriction.

2. Temporal concordance: Quantitative evidence for temporal concordance is limited or nonexistent in the literature, therefore a proposed experiment to prove temporal concordance uses a stimulus of the AOP at a singular dose. After the stimulus is applied, measurements of endothelin and measurements of afferent arteriole diameter are taken to demonstrate that an increase of endothelin occurs before or at the same time that afferent arteriole vasoconstriction occurs. Endothelin levels can be measured using ELISA.

3. Incidence concordance: Quantitative evidence for incidence concordance is limited or nonexistent in the literature, therefore a proposed experiment to prove incidence concordance uses a stimulus of the AOP at a singular dose. After the stimulus is applied, the incidence of each of the key events in the KER are measured to prove that increased endothelin occurs for frequently or the same amount as the increase in afferent arteriole vasoconstriction.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Inconsistencies:

Despite endothelin-1 being a well established potent vasoconstrictor, binding of endothelin to ET_B receptor has shown potential vasodilatory effects demonstrating that endothelin-1 may play a role in both vasoconstriction as well as vasodilation of the arterioles. This is due to endothelin binding to ET_Breleases nitric oxide and prostaglandins, both being vasodilators (Guan, 2017).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

KER4: Increased, Endothelin leads to Increased, afferent artery vasoconstriction

In an in vitro model using a blood-perfused juxtamedullary nephron it was shown that at using endothelin-1 at a concentration of 10nM elicited an 83% reduction in the diameter of the afferent arterioles compared to the control. This same experiment was performed at a lower concentration of 1nM, where vasoconstriction was also demonstrated (Guan, 2011).

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

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

Guan, Z., & Inscho, E. W. (2011). Endothelin and the renal vasculature. Contributions to nephrology, 172, 35–49. https://doi.org/10.1159/000328720

Guan, Z., VanBeusecum, J. P., & Inscho, E. W. (2015). Endothelin and the renal microcirculation. Seminars in nephrology, 35(2), 145–155. https://doi.org/10.1016/j.semnephrol.2015.02.004

Kawanabe, Y., & Nauli, S. M. (2011). Endothelin. Cellular and molecular life sciences: CMLS, 68(2), 195–203. https://doi.org/10.1007/s00018-010-0518-0