Molecular mechanisms of platelet-mediated neutrophil extracellular traps formation during acute kidney injury

• Applicant: Professor Dr. Jan Rossaint
• Subject Area: Anaesthesiology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264341202

Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with a high mortality. The disease can be caused by different insults including ischemia-reperfusion injury as well as sepsis. Neutrophils play an important role in the pathogenesis of AKI. Neutrophils may interact with platelets during inflammation and this cell-cell interaction can modulate leukocyte recruitment and neutrophil activation including neutrophil extracellular trap formation and ROS production. However, it is still unknown whether platelets interact with neutrophils during the development of AKI and whether this interaction activates neutrophils and induces NET formation. Furthermore, the molecular mechanisms of platelet-induced NET formation are unclear. The first aim of this proposal is to investigate the role of platelets and NET formation during AKI. For this purpose, two mouse models of AKI will be used to analyze neutrophil recruitment and NET formation in the kidney as well as platelet-neutrophil aggregate formation. To investigate which molecules are involved in this cell-cell interaction, gene-deficient mice, blocking antibodies and specific pharmacological inhibitors will be used. The second aim focuses on the consequences of NET degradation and impaired NET formation for leukocyte recruitment and disease progression of AKI. We will modulate NET structures by using different reagents and gene-deficient mice and analyze the different steps of leukocyte recruitment into the kidney during AKI. For this, intravital microscopy of the kidney and a new flow-cytometry based method will be used. The results from theses proposal will help to identify new therapeutic directions for future clinical treatment strategies for patients with AKI.

• DFG Programme: Research Grants