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Inflammatory response identified as a possible cause of organ damage / Study opens up new therapeutic approaches / Published on November 27, 2025, in the European Heart Journal

People with diabetes have a significantly increased risk of heart failure and kidney disease—even when their blood sugar levels are well controlled. An international research team led by the Medical Center – University of Freiburg has identified a key immune mechanism that may explain these complications. The study shows that the enzyme peptidylarginine deiminase 4 (PAD4) activates certain immune cells, thereby triggering inflammatory processes that damage the heart and kidneys. The results were published on November 27, 2025, in the European Heart Journal. 

“Our findings show for the first time that PAD4 is a key link between diabetes and inflammatory processes in the heart and kidneys,” says study leader Dr. Lukas A. Heger, a specialist at the Department of Cardiology and Angiology at the Medical Center – University of Freiburg. “This misdirected immune response could explain why many patients develop severe complications despite good blood sugar control.”

Evidence from patient samples and animal models

The study focuses on the enzyme PAD4, which plays a key role in the activation of immune cells. The researchers were able to show that elevated glucose levels immediately activate so-called neutrophils. These immune cells then release pro-inflammatory signaling molecules as well as neutrophil extracellular traps (NETs). This process is regulated by PAD4 and leads to a persistent inflammatory response that not only fights pathogens but also damages healthy tissue.

In heart tissue from patients with heart failure, the researchers found significantly more NET deposits in those with additional diabetes than in patients without diabetes. The more pronounced the deposits were, the more impaired heart function was. These observations were confirmed in animal models: Only mice with active PAD4 developed typical diabetes-related damage such as reduced cardiac output, tissue scarring, and impaired kidney function.

New Perspectives for Treatment

The results show that organ damage in diabetes is not caused solely by elevated blood sugar levels, but is largely mediated by a PAD4-dependent immune response. The heart and kidneys are particularly affected.

“PAD4 acts like a switch that programs neutrophils for inflammation,” says Prof. Dr. Dirk Westermann, Medical Director of the Department of Cardiology and Angiology at the Medical Center – University of Freiburg. “Targeted inhibition of this enzyme could help prevent heart and kidney damage in diabetes in the future.”

The study thus opens up new therapeutic perspectives that go beyond mere blood sugar control.