Defining the interaction of platelets, neutrophil extracellular traps and thrombo-inflammation in diabetic kidney disease

• Applicants: Professor Dr. Berend Isermann; Dr. Shrey Kohli
• Subject Area: Toxicology, Laboratory Medicine ; Endocrinology, Diabetology, Metabolism
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524693705

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease. This makes DKD a major cause of morbidity and mortality in diabetic patients and increases the burden on the healthcare system. Glomerular endothelial dysfunction and associated coagulation activation have been linked with glomerular filtrations barrier (GFB) disruption and DKD progression. While a homeostatic function of soluble coagulation regulators at the GFB independent of hemostasis has been described, mechanistic studies linking platelet activation, thrombo-inflammation and glomerular endothelial dysfunction are missing. Thrombo-inflammatory mechanisms are characterized by an interaction of platelets with innate immune cells, such as neutrophils. Additionally, DKD severity is associated with accumulation of immune cells in the kidney. Neutrophils can induce inflammation by formation of neutrophil extracellular traps. In our preliminary work we detected NETs in glomeruli of diabetic mice. Platelets exacerbate glucose-induced NET-formation on glomerular endothelial cells and in glomeruli in vivo, which is associated with increased NLRP3 inflammasome activation and impaired endothelial function (reduction of eNOS, KLF2, KLF4, TM). Additional data suggest that NET formation not only leads to histone citrullination, but also to citrullination of endothelial proteins. Based on these preliminary data, we hypothesize that platelets interact with neutrophils, promoting formation, accumulation, and stabilization of NETs which exacerbate renal sterile inflammation (NLRP3 inflammasome) and impairs endothelial function in DKD. In order to address this hypothesis, we propose the following aims: (1) Defining the regulation, mechanistic relevance, and translational importance of platelet associated NET-formation in DKD; (2) Establish the relevance of the NLRP3 inflammasome for platelet and NET mediated sterile inflammation in DKD; (3) Characterizing the mechanistic relevance of the endothelial Klf-2/4-thrombomodulin axis in platelet-NET-dependent endothelial dysfunction and renal thrombo-inflammation; (4) Characterizing the role of protein citrullination for endothelial dysfunction and renal thrombo-inflammation; these studies will provide new insights into the mechanisms of glomerular thrombo-inflammation in DKD and evaluate the relevance of platelet and/or NET inhibition to prevent or reduce glomerular endothelial dysfunction in DKD. These will thus provide insights into perpetuating inflammatory mechanisms at the GFB, which may be therapeutically targeted.

• DFG Programme: Research Grants