Mechanisms of renoprotection: on the anti-inflammatory roles of thrombomodulin and soluble FLT1 in renal disease

Abstract

Chronic kidney disease (CKD) has a major impact on the mortality and quality of life of patients. Mounting evidence indicates an important role of chronic inflammation in the development of CKD. This thesis evaluated the feasibility of stimulating the function of two anti-inflammatory proteins, thrombomodulin and soluble fms-like tyrosine kinase-1 (sFLT1), as novel therapeutic strategies for CKD. In the first part, the clinicopathologic significance of aberrant thrombomodulin expression was evaluated in various renal diseases. Here, a dysregulation of glomerular thrombomodulin expression was associated with increased local macrophage infiltration and endothelial dysfunction in the kidneys of patients with diabetic nephropathy and preeclampsia. In the second part, we demonstrated that treatment with the VEGF inhibitor sFLT1 ameliorates tissue damage and improves organ function in mouse models of chronic inflammatory skin and renal disease. In both models, treatment with sFLT1 dampened the infiltration of immune cells within the affected tissues. Finally, we demonstrated that sFLT1 directly binds to the cell surface of macrophages in vitro, offering a novel anti-inflammatory mechanism of sFLT1. Together these works indicate potent anti-inflammatory effects of thrombomodulin and sFLT1, thereby providing a basis for the further development of TM- and sFLT1-based therapies to prevent disease progression of CKD in patients.