Proteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by... Show moreProteinuria is an independent risk factor for the progression of kidney injury, cardiovascular morbidity, and overall mortality. In this thesis, the pathways leading to proteinuria are explored by revisiting elements previously considered essential, investigating known pathways, and identifying new players in the field of proteinuria. First, a zebrafish embryo model for developing new therapeutic options for the rare but devastating disease of nephropathic cystinosis is presented. The studies presented in thesis also investigate loss of heparan sulphate glycosaminoglycans in a zebrafish embryo model and in multiple osteochondroma patients. These studies show that loss of heparan sulphate glycosaminoglycans does not always lead to proteinuria. Next, dynamin is described as a promising potential therapeutic target for treating proteinuria. The final study introduces transmembrane protein 14A as an essential factor in maintaining glomerular filtration barrier function. Overall, these studies contribute to elucidating the pathways to proteinuria in the hope to keep advancing the field towards targeted treatment of proteinuria for the benefit of our patients. Show less
Preeclampsia is a syndrome of pregnancy characterised by hypertension and proteinuria and occurs in up to 5 percent of pregnant women. The pathophysiology of preeclampsia has not been fully... Show morePreeclampsia is a syndrome of pregnancy characterised by hypertension and proteinuria and occurs in up to 5 percent of pregnant women. The pathophysiology of preeclampsia has not been fully elucidated yet. The endothelium is known to play a key role in the pathogenesis and levels of vascular endothelial growth factor are decreased due to an angiogenic imbalance. In the first part of this thesis, genes associated with preeclampsia were investigated through meta-analysis; genes within the coagulation and immunology domains remained significantly associated with preeclampsia after meta-analysis. In the second and third part of this thesis, the possible role of a key regulator of coagulation and immunology on the endothelium, thrombomodulin, in preeclampsia was investigated in the placenta and the kidney. Diminished placental thrombomodulin expression was associated with the angiogenic imbalance of preeclampsia. Next, in the fourth part of this thesis the interplay between podocytes and endothelial cells in the glomerulus during the anti-angiogenic conditions in preeclampsia was reviewed. In the final part of this thesis the splicing pattern of vascular endothelial growth factor was investigated throughout different examples of glomerular disease. Show less
In this thesis several aspects of SLE were investigated. First, we studied interobserver agreement concerning class III/IV lupus nephritis lesions in a renal biopsy and found that agreement was... Show moreIn this thesis several aspects of SLE were investigated. First, we studied interobserver agreement concerning class III/IV lupus nephritis lesions in a renal biopsy and found that agreement was poor. This seemed, in part, due to inconsistent or ambiguous definitions as provided in the 2004 ISN/RPS classification. This led us to re-evaluate the current classification with an international group of highly experienced nephrologists. Second, we compared and summarized the lupus nephritis management guidelines that were published in 2012. Third, we studied microchimerism in peripheral blood of women with SLE and control subjects. We found that women with SLE have more microchimerism in their peripheral blood than control subjects. Then, we studied microchimerism in the peripheral blood of women with SLE and control subjects during and after pregnancy. We found that only just after delivery did the SLE patients have more chimeric cells in the granulocyte fraction than control subjects. These results suggest that after pregnancy chimeric cells become undetectable in peripheral blood, but possibly remain at other sites, only to re-emerge after un unknown trigger. Finally, we compared sporadic and familial lupus nephritis to find that, although there were clinical differences, no differences in histology or genetic background were apparent. Show less
__Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival, but when the kidneys fail to manufacture the proper kind of... Show more__Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival, but when the kidneys fail to manufacture the proper kind of blood neither bone, muscle, gland nor brain can carry on__. This quote from Homer Smith's book 'From Fish to Philosopher' indicates the importance of the kidney for the maintenance of the harmonious composition of body fluids __ a function the kidney performs in a way that joins efficacy with elegance. Some of these processes are lined out in this thesis. The first chapter gives an introduction to kidney development, anatomy, and function, as well as a description of malfunction of the kidney, focusing on the development of proteinuria and failure of kidney transplants. The subsequent chapters describe studies that have been performed to investigate the biological mechanism that underly the development of proteinuria and long-term renal transplant failure. Show less
The main focus of this thesis is the study of the role of Wnt5 during central nervous system development in Drosophila. Wnt5, previously known as DWnt3, was identified as a gene required for proper... Show moreThe main focus of this thesis is the study of the role of Wnt5 during central nervous system development in Drosophila. Wnt5, previously known as DWnt3, was identified as a gene required for proper central nervous system development. The finding that a Wnt protein, traditionally associated with other developmental functions, is also required for axon guidance during late embryogenesis provided exciting new insights in the broad mechanisms that are used to establish the stereotypical neuronal connectivity of the central nervous system. Subsequent experiments described in this thesis reveal that, during embryonic development of the central nervous system, Wnt5 seems to be acting through an alternative pathway which involves src mediated signaling through the fractured tyrosine kinase RYK/Drl. Furthermore, we show that Wnt5 signaling through RYK/Drl is also required for proper muscle development suggesting a common signaling pathway required for muscle attachment site selection as well as axon guidance. Show less
