Purpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping... Show morePurpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations. Methods This double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18-50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-beta; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort. Results rHuEPO increased P-selectin (+ 7.8% (1.5-14.5),p = 0.02) and E-selectin (+ 8.6% (2.0-15.7),p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0-24.3%),p = 0.0004) higher E-selectin and 32.1% ((4.6-66.8%),p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group. Conclusion In conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use. Show less
In this thesis we investigated various mechanisms by which the immune system plays a role in the development of diabetic nephropathy. In chapter 2 we describe that APOC1-tg mice develop... Show moreIn this thesis we investigated various mechanisms by which the immune system plays a role in the development of diabetic nephropathy. In chapter 2 we describe that APOC1-tg mice develop glomerulosclerosis at 15 months of age, with increased number of glomerular macrophages. Our results suggest that apoCI may exacerbate the development of DN by increasing the inflammatory response in activated glomerular macrophages. In chapter 3 we demonstrate that sFLT-1 significantly improves kidney function, resolves diabetes-related kidney damage, and reduces endothelial cell activation and inflammation, suggesting that sFLT-1 can reduce the severity of DN by reducing glomerular inflammation and supporting cellular repair mechanisms.In chapter 4 we show that reducing endoglin levels diminished VEGF-A-induced endothelial activation by increasing pAkt and reducing pATF-2. These data suggest that targeting endoglin may have therapeutic value in patients who are at risk for developing DN.In chapter 5 we demonstrate that renal complement activation is associated with more severe classes of DN, reduced kidney function, and the presence of histological lesions.In chapter 6 we describe that transfecting APOC1-tg mice with sFlt-1 does not accelerate development of glomerulosclerosis, but lowered the number of glomerular macrophages. These data suggest that sFLT-1 treatment has an anti-inflammatory effect. Show less
Bus, P.; Scharpfenecker, M.; Wilk, P. van der; Wolterbeek, R.; Bruijn, J.A.; Baelde, H.J. 2017
