Chapter 7 128 Regarding the role of negative charge and specifically, that of heparan sulphate glycosaminoglycans in the glomerular filtration barrier, it would be most interesting to investigate which proteins or circulating factors (next to the previously identified heparanase) influence its expression and degradation.(130, 131) Also, the changes in ligand binding ability of the glomerular glycocalyx might reveal more about the role of HS-GAG in maintaining GFB integrity. Both large (dynamin) and small (Rho family) GTPases have already shown promise as therapeutic targets in preventing or even attenuating renal damage in proteinuric animal models. Compounds acting on these targets are yet to enter safety and efficacy testing for human trials but are an elegant example of translational medicine from a pathophysiological point of view. New potential targets, such as TMEM14A and its uncharted regulatory proteins, are being discovered at a high rate. As glomerular expression levels in human proteinuric kidneys in our TMEM14A experiments differed depending on etiology, it is conceivable that this particular pathway might not be of interest to all proteinuric diseases, but only a subset like diabetic nephropathy. It can be tentatively stated that the further identification of its protein-protein interactions including up- and downstream effects will reveal if this pathway to proteinuria is indeed a feasible therapeutic option. The zebrafish experimental animal model has presented itself as an expedient model for both identifying and testing therapeutic targets. Further innovations in experimental animal models and especially in non-animal models such as organoids, will hopefully increase the rate of discovering potential targets and screening the effectiveness of therapeutic compounds. Thus, by further illuminating the pathways to proteinuria we hope to keep advancing the field towards targeted treatment of proteinuria for the benefit of our patients.
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