New anti-inflammatory approach may damage kidneys, Monash scientists find

L-R: First co-authors Drs Jay Jha and Jakob Østergaard,
lead author Professor Karin Jandeleit-Dahm, CCS Diabetes

by Anne Crawford

A study by Monash University Department of Diabetes researchers suggests that a new anti-inflammatory drug approach developed to counter inflammation and heart disease may be harmful to kidneys.

The approach uses an inhibitor called MCC950 to counter the action of NLRP3 inflammasomes. Inflammasomes are a group of proteins in the body activated by the immune system to induce inflammation to fight infection.

Professor Karin Jandeleit-Dahm, who led the Monash study, said there was increasing interest in the inhibition of the NLRP3 inflammasome as a new drug target and that recent studies had suggested such an approach could prevent heart disease. MCC950 had been shown elsewhere to be effective in many inflammatory diseases and is in clinical development for Parkinson’s disease.

Her group collaborated with Baker Institute scientists Professor Judy de Haan and Dr Arpeeta Sharma who had been working on the new inhibitor MCC950, to investigate its effect on diabetes-associated atherosclerosis.

Using a similar set-up – the same dose of MCC950 in the same diabetic model – Professor Jandeleit-Dahm found that NLRP3 inhibition had an adverse effect on diabetic kidney disease despite having beneficial effects in blood vessels.

“This drug blocks the inflammasome but we saw an increase in other inflammatory markers such as macrophage infiltration, oxidative stress and in structural terms, there was of more fibrosis and scar tissue formation in the kidney,” she said.

“This raises some warning signals that one has to be really careful with this approach – one organ could react in one way and another in another way.

“One has to be careful in general with new drug developments that look promising in one area, but the body is a system of multiple organs so you always have to assess whether there are deleterious effects on other systems.”

Professor Jandeleit-Dahm cautioned that her study only looked only at one dose of the drug and only one representative of the inflammasome inhibitors

The results called for a detailed evaluation of NLRP3 inflammasome blockers, she said.
 
“Definitely any large clinical trial with this drug should assess the effects on the kidneys as well.”  

Professor Jandeleit-Dahm’s group will further investigate using different doses of the inhibitor and other inflammasome inhibitors currently being developed.

First co-authors on the study were Dr Jakob Østergaard from the highly regarded Steno Diabetes Center Aarhus at the Aarhus University Hospital, Aarhus, Denmark and Dr Jay Jha, Monash Department of Diabetes.

Reference  
Østergaard, J. A., Jha, J. C., Sharma, A., Dai, A., Choi, J., de Haan, J. B., Cooper, M. E., & Jandeleit-Dahm, K. (2022). Adverse renal effects of NLRP3 inflammasome inhibition by MCC950 in an interventional model of diabetic kidney disease. Clinical science (London, England : 1979), 136(2), 167–180. https://doi.org/10.1042/CS20210865