Cells with stress: predicting drug-induced liver and kidney damage

How can we prevent drug-induced liver and kidney damage? PhD candidates Marije Niemeijer and Lukas Wijaya investigated what happens in the cells during the onset of this damage: a stress response. Both focused on a different subtopic and made some interesting discoveries.

When something bad happens, we get stressed. The same applies to a liver or kidney cell, tells Wijaya. ‘Albeit on a smaller scale. When a compound disturbs the balance of the cell, the cell will try to restore it.. Niemeijer: ‘The cell can produce all kinds of proteins with different functions to try and shift back to its normal condition. This reaction is called a stress response.

Predicting liver or kidney damage

Niemeijer en Wijaya wanted to learn more about the activation of these stress responses. ‘It would give us a better understanding of the mechanisms that contribute to drug-induced liver and kidney damage,’ says Niemeijer. ‘And those insights may aid, for example, in the prediction of liver or kidney damage during drug development and safety assessments.’

A kidney is not just a bean

Although both researchers focused on stress responses, they each chose a different subtopic. Wijaya looked at stress responses in different regions of mainly the kidneys. ‘From the outside, the kidneys look just like a red bean,’ he explains. ‘But a kidney has different regions made up of different tissue types. I showed that each of those tissue types reacts differently upon injury. Some are less, some are more sensitive, some help injured regions to recover and some don’t do anything at all.’

‘If we only consider an injured kidney as a whole, we might underestimate the differences between tissues or regions.’

And that’s an important realisation, according to Wijaya. ‘If we study an injured kidney only as a whole, we see a mixed response that is the sum of all those smaller responses. This means we might underestimate the differences between those different tissues or regions. If we know how each specific region reacts to injury, we will have a much more detailed mechanistic understanding.’

Different patients, different stress responses

Niemeijer studied the differences in stress responses upon drugs between patients. She hereby focused on liver cells. ‘I found quite large differences,’ she tells. ‘If cells of different patients behave differently when they’re stressed, they may also be more or less prone to drug-induced damage. That’s important information for the development of new drugs: you always want to take these differences into account to be on the safe side, for example when testing new drugs in humans.’

Stress responses at a gene level

Besides this, Niemeijer was also interested in how stress responses are regulated on a gene level. ‘The proteins released during a stress response, originate in the DNA. You can see the DNA as a recipe book for our proteins, with the genes as recipes. When stressed, the cells express certain genes. These parts of the DNA are then copied into RNA. Next, the cells read these RNA codes or “recipes” and translate them into proteins.’

Wijaya and Niemeijer in the lab

Niemeijer analysed which RNA was present in liver cells after stress responses caused by different drugs. This way, she could also retrace which genes were expressed. Furthermore, Niemeijer used inhibitors to deactivate certain genes and checked how this affected the stress response. ‘The inhibitors prevent the cell from converting a certain piece of RNA into proteins. This learns us more about the influence of a certain gene. What happens to the activation of a stress response when that gene is not expressed?’

Making real-life organ models

Both Niemeijer and Wijaya are continuing their career in Leiden as postdocs. Wijaya: ‘We are now trying to create better and more realistic 3D organ models, called organoids. I am, for example, trying to create kidney organoids that reflect and reassemble the structure of real kidneys as well as possible.’

‘We hope that realistic organ models one day can replace animal testing.’

Niemeijer is improving liver organoids for drug safety testing. ‘We’re using liver cells that are derived from stem cells. Here, we build in reporters, proteins with a fluorescent tag, that help us monitor stress responses. That way, we can screen new drugs and chemicals to see whether they are inducing any kind of stress response that could indicate harmful side effects.’ Wijaya: ‘With these advancements, organoids can hopefully one day replace animal testing and become a realistic alternative to real human organs in research.’

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