Activation of Protein kinase C leads to Kidney Failure

Hannah Szalay

Kidney failure is of interest for human health risk assessment. Kidney failure is an important human health issue associated with numerous causes such as diabetes, high blood pressure, dehydration, smoking, and chemicals/pharmaceutical drugs. People suffering from chronic kidney disease (CKD) essentially undergo kidney failure. Once kidney function is lost it cannot return to normal function therefore there is a need to investigate the molecular mechanisms of kidney failure to prevent it from occurring. Between 1990 and 2016 there was an 88% increase in the incidence of kidney failure (Kuma, 2022). Considering the potential applications of the prototypical stressors of this AOP, it may be of regulatory interest for risk assessment decisions to know if they will or will not induce the AO of kidney failure. Kidney failure has major global impact on health and morbidity while also being an associated risk factor for cardiovascular disease, the leading cause of death globally (GBD Chronic Kidney Disease Collaboration, 2020).

The MIE outlined in this AOP is activation of protein kinase C (PKC), belonging to the family of protein kinase enzymes that is involved in numerous cellular/biological activities including gene expression, protein secretion, proliferation, and inflammatory responses (Gould, 2008). The MIE is induced through exposure to a number of different prototypical stressors namely phorbol esters, such as PMA, which are routinely used in biomedical settings. However, phorbol esters, along with other prototypical stressors have numerous other potentials uses due to insecticidal and biopesticide properties (Goel, 2007). Another example of a PKC activator includes Bryostain-1, which is currently undergoing clinical trials for its use as an anticancer therapy (Tran, 2024). The AO outlined is kidney failure characterized by improper/irregular function of the kidneys. This typically means the kidneys are no longer excreting waste from the body causing a build-up of toxic substances/chemicals/molecules etc. in the blood (National Cancer Institute, 2024). Kidney failure ultimately leads to death and is progressive typically first developing as CKD (Webster, 2017). Major KE’s of this AOP include increased edn1 gene expression which codes for endothelin, increased endothelin protein levels which is a well-established potent vasoconstrictor, increased afferent artery vasoconstriction, and decreased glomerular filtration.

 The overall WoE supporting the AOP is moderate. Most of the KER have high biological and moderate quantitative understanding, however all of the KER have low empirical evidence to support the key event relationships. Therefore, the overall weight of evidence given to the AOP is moderate because every KE and KER is very well established and biologically plausible however quantitative data is limited or nonexistent to provide WoE. Since there is limited empirical data for dose, time, and incidence concordance it is the largest knowledge gap existing for the AOP.

The AOP of activation of protein kinase C leading to increased kidney failure is specific to vertebrates, and not life stage or sex specific. Overall WoE for the AOP is moderate. All KE are essential for the pathway. All of the KER in the pathway have high biological plausibility. Most of the KER have moderate quantitative understanding. Most of thr KER have low empirical evidence to support the relationships. So despite the minimal experimental evidence to. support the dose, time, and incidence concordance of the KER, the essentiality and biologically plausibility having high WoE establishs moderate confidence in the AOP. Experiments would need to be performed to prove the empircal evidence for the KER of the pathway in order to give the AOP a WoE of high. These experiments would include both time and dose concordance experiments along with incidence concordance experiments. 

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