Molecular mechanisms of uremia-associated modulation of inflammation in chronic kidney disease.

• Applicant: Professor Dr. Alexander Zarbock
• Subject Area: Anaesthesiology
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261914061

Loss of renal function is associated with a pro-¬inflammatory milieu and a concomitantly impaired immune system. In patients with chronic kidney disease (CKD), the uremia-associated defect in the immune system has a broad clinical impact on morbidity and mortality. These patients are highly susceptible to infections and have an increased risk of atherosclerosis. Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counter-receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several pathways leading to integrin activation, leukocyte adhesion to endothelium, and transmigration into inflamed tissue. However, the molecular mechanisms of uremia-associated altered leukocyte recruitment and inflammatory response are yet unknown. Therefore, the aim of the proposal is to identify how chronic uremia in the context of CKD may affect integrin activity and the different steps of leukocyte recruitment by using gene-deficient mice, retrovirus technology, and biochemical methods. As the levels of fibroblast growth factor (FGF)-23 increase in patients with CKD, we will investigate the effects of FGF23 on leukocyte functions. In addition, we will perform a clinical trial and confirm our findings in patients with CKD. Further understanding of the role of uremia-associated altered leukocyte recruitment and activation is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Hermann Pavenstädt