- The Protein C system in renal disease
- Award date
- 8 July 2016
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Mounting evidence shows that coagulation and inflammatory processes are closely intertwined phenomena. As a result, most elements of the coagulation cascade and their negative regulators have been implicated in inflammatory and immune processes. The research presented in this thesis addresses the roles that different elements of the Protein C system (activated Protein C, APC; the endothelial Protein C receptor, EPCR; thrombomodulin and Protein S) play in renal diseases, as well as in renal allograft rejection, with an emphasis on the inflammatory effects of these proteins.
We have demonstrated that APC protects mice against ischemia/reperfusion injury, independently from its anticoagulant activity.
In renal transplantation, elevated expression and urinary shedding of EPCR were observed, resulting in elevated levels of soluble urinary EPCR which could potentially be used as a non-invasive biomarker for antibody-mediated rejection.
During acute pyelonephritis, mice lacking the lectin-like domain of thrombomodulin showed elevated bacterial loads in their bladder and kidneys. This was accompanied by reduced inflammation and neutrophil infiltration, demonstrating that the lectin-like domain of thrombomodulin is critically involved in host defence against E. coli-induced acute pyelonephritis.
We have evidenced the first causal link between metalloproteinase(ADAM17)-driven EPCR shedding and diabetic nephropathy. Namely, ADAM17-driven EPCR shedding contributes to the loss of endothelial phenotype in glomerular endothelial cells incubated under hyperglycaemic conditions.
Finally, we have shown that diabetic patients with albuminuria displayed elevated levels of circulating TAM receptors (ligands of protein S). ROC curve analysis suggest that excretion of TAM receptors may serve as a diagnostic marker for DN.
- Research conducted at: Universiteit van Amsterdam
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