General introduction and outline 13 1 translation resulted in proteinuria in a zebrafish embryo model. Next, differential mRNA and protein expression are investigated in spontaneously proteinuric rats. In this step, the temporal relationship between the onset of proteinuria and relative loss of expression is assessed. Furthermore, the translation to human proteinuric kidney disease is made by examining the protein expression of the investigated targets in kidney biopsies from patients with proteinuric renal diseases. These methods were used both to investigate known proteins, such as dynamin, but has also uncovered previously unknown proteins to be involved in the development of proteinuria, such as transmembrane protein 14A. Aim and outline of the thesis In this thesis, the pathways leading to proteinuria are explored. To identify potential pathways, elements considered essential are revisited, known pathways are explored further, and new players in the field of proteinuria are identified. First, a zebrafish embryo model to assess both glomerular filtration barrier function and tubular reabsorption mechanisms is presented in Chapter 2. The use of this model for developing new therapeutic options for the rare but devastating disease of nephropathic cystinosis is presented. In Chapters 3 and 4, the loss of heparan sulphate glycosaminoglycans is investigated. Heparan sulphate glycosaminoglycans have long been considered essential for adequate glomerular filtration function. In Chapter 3, a global heparan sulphate glycosaminoglycan deficiency on the development of proteinuria was shown to not affect glomerular filtration barrier function nor tubular reabsorption mechanisms. The used dackel zebrafish embryo mutant has a biallelic germline mutation in the zebrafish homologue of EXT2, resulting in truncated and functionally impaired heparan sulphate glycosaminoglycan chains. Chapter 4 continues with investigating the loss of heparan sulphate glycosaminoglycans in multiple osteochondroma patients, who have a heterozygous mutation in either EXT1 or EXT2. Here, no proteinuria, a specific renal phenotype, or changes to the glomerular endothelial glycocalyx were observed. In Chapter 5, the role of dynamin in proteinuric conditions and human disease is explored. Dynamin has been identified to play an important role in maintaining glomerular filtration barrier structure and function. In this chapter, this role is further specified as a dynamically regulated protective mechanism against the development of proteinuria.
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