New antibody-based strategy shows promise in preventing kidney damage and fibrosis
A collaborative study led by researchers at IGP, Karolinska Institutet, and Northwestern University, reveals a promising new therapeutic strategy to protect the kidneys from progressive damage and fibrosis, conditions that underlie chronic kidney disease. The findings were recently published in the Journal of Clinical Investigation.
Riikka Pietilä and Marie Jeansson (photos: private)
Chronic kidney disease affects over ten percent of the global population and is projected to become the fifth leading cause of death worldwide by 2040. Despite current therapies, patients frequently experience continued kidney deterioration, culminating in end-stage renal disease that requires dialysis or transplantation.
In the new study, the research team demonstrates that activating a key endothelial receptor, TIE2, can protect kidney blood vessels, preserve capillaries, and reduce fibrosis, i.e. tissue scarring, in an experimental model of chronic kidney disease.
The researchers achieved TIE2 activation using an innovative antibody, known as ABTAA, which binds and clusters the vascular protein angiopoietin-2, transforming it from an antagonist into an agonist. By turning this natural inhibitor into a strong activator of TIE2, ABTAA not only prevented vascular injury but also reduced kidney fibrosis and tubular cell damage.
“By protecting the vasculature, we were able to safeguard the kidney’s microenvironment and block the signaling pathways that drive fibrosis. Our findings suggest that TIE2 activation using ABTAA could be developed into a new therapeutic approach for chronic kidney disease, an area where treatment options remain limited,” said Marie Jeansson, corresponding author and Associate Professor at IGP.
The study also uncovered new insights into the mechanisms of kidney fibrosis. Contrary to previous assumptions, the researchers found that endothelial dysfunction does not promote fibrosis directly by the transition of endothelial cells into mesenchymal cells, the cell type involved in fibrosis.
“One of the most striking findings is the mechanistic insight that we gained. We could show that endothelial dysfunction drives fibrosis indirectly by altering tubular cell signaling, rather than through direct trans-differentiation of endothelial cells. Instead, it triggers pro-fibrotic signals from tubular epithelial cells. Importantly, TIE2 activation could also suppress this pathway, thereby reducing fibrosis. This shifts how we think about the disease and where to intervene,” says Riikka Pietilä, researcher at IGP and first author of the study.
In summary, the results from the study highlight vascular protection as a crucial strategy in halting the progression of chronic kidney disease and point to ABTAA as a promising candidate for future clinical development.