Chapter 7 124 enzymes of heparan sulphate glycosaminoglycans was investigated in patients with multiple osteochondromas. Multiple osteochondroma is an autosomal dominant disease caused by a mutation in either EXT1 or EXT2 leading to the formation of, as the name implies, multiple osteochondromas.(59, 60, 69) We investigated a cohort of multiple osteochondroma patients in a cross-sectional manner and found that they did not exhibit proteinuria or an altered endothelial glycocalyx. Also, we investigated a historic cohort of patients who had both an osteochondroma resection and kidney biopsy in their medical history. Upon re-examination of the slides, no specific glomerular morphological changes were observed. One patient did show a glomerular phenotype on electron microscopy similar to that of a described case of ‘MO glomerulopathy’ with focal fibril deposition. (56) The rare cases of MO glomerulopathy are hypothesized to be caused by local loss of heterozygosity. In conclusion, the results from these studies support the growing body of evidence that loss of heparan sulphate glycosaminoglycans does not result in loss of glomerular filtration barrier integrity, despite resulting in loss of negatively charged sites. Dynamin and GTPases One of the most promising potential therapeutic targets for the treatment of proteinuria is dynamin. Dynamin is known for its role clathrin-mediated endocytosis and synapse junction vesicle budding. Dynamin is a GTPase that forms a helical polymer around the neck of budding vesicles and causes membrane scission (120). In the kidney, it has been identified to be involved in the turnover of nephrin, direct interaction with actin and actin-regulatory proteins, and the endocytosis of albumin by podocytes. (11, 12, 14, 74) Its function depends on its oligomerization state and on whether it is cleaved by cathepsin L. (13, 14, 87, 121, 122) Schiffer et al. and Ono et al. demonstrated the potential of dynamin as a therapeutic target by treating several proteinuric animal models with Bis-T-23, which stimulates dynamin oligomerization. After administration, proteinuria decreased and the ultrastructure of podocyte foot processes was restored.(75, 76) In chapter 5, we show that glomerular dynamin mRNA expression increases before the onset of proteinuria and that both Dynamin and Cathepsin L protein expression is increased in proteinuric patients with various different underlying diseases. These results further support the suggested protective and dynamic role of dynamin in preventing the development of proteinuria through its interaction with the actin cytoskeleton and nephrin before the onset of proteinuria. As this mechanism also seems to play a role in proteinuric patients, this study further propagates the concept that dynamin and its regulation are potential therapeutic targets for the treatment of proteinuria.
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