Crystal clots as therapeutic target in cholesterol embolism-related acute kidney injury

• Applicant: Professor Dr. Hans-Joachim Anders
• Subject Area: Nephrology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273724388

Cholesterol embolism syndrome (CES) is a complication of advanced atherosclerosis in which cholesterol crystals are released from atheroma plaques, especially from the aorta, into the blood, which then leads to embolization and infarction. The brain (stroke), eyes (blindness), intestines (peritonitis), kidneys (acute renal failure) and especially the lower extremities (blue toe syndrome) are frequently affected. Although CES is often fatal, little is known about the cellular and molecular pathogenesis due to the lack of an animal model. In preliminary work, we have therefore established a reliable animal model of CES of the kidneys in mice, which also allows investigations in common gene-deficient or transgenic mouse lines. The main endpoints are the glomerular filtration rate measured in the awake and freely moving animal as a clinically relevant parameter of renal function, defining acute renal failure, and the size of the renal infarcts. Our preliminary work indicates a special role of platelet activation and aggregation in the development of crystal thrombosis as a major damage mechanism of this disease. Therefore, the role of specific platelet activation pathways in CES will be systematically investigated for the first time as part of the project applied for here. The following aspects will be investigated: 1. The role of mitochondria in blood platelets with cyclophilin D as a molecular target to prevent platelet necrosis in the formation of crystal thrombosis. 2. The role of surface receptors of blood platelets that interact with collagen and fibrin, e.g. glycoprotein-6, to prevent platelet aggregation in the formation of crystal thrombosis. 3. The role of integrins on the surface of platelets, e.g. integrin alpha5 and beta 1, in preventing platelet aggregation in the formation of crystal thrombosis. This project will produce data that will provide the first insights into selective interventions with molecular targets on platelets to prevent crystal thrombosis. The aim is to investigate the molecular pathogenesis of this potentially fatal but largely unexplored disease and to test innovative therapeutic options in a new animal model.

• DFG Programme: Research Grants