7 General discussion and future perspectives 127 the necessity to inject a dextran mixture but has no simultaneous assessment of tubular reabsorption function. With the introduction of this model, measuring the loss of fluorescence intensity in the zebrafish eye was also established as an indirect measurement of loss of GFB integrity. (45) Spontaneously proteinuric rat model Laboratory rats (Rattus norvegicus domestica) are perhaps the most well-known experimental animal model, after mice. The first documented experiment on rats was performed in France back in 1856 and consisted of the examination of the effects of adrenalectomy.(128) Rats were also ahead of zebrafish regarding space travel, as they had joined Soviet space dogs Belka and Strelka aboard the Sputnik 5 in 1960. In this thesis, the spontaneously proteinuric Dahl salt-sensitive rat strain was compared with nonproteinuric spontaneously hypertensive rats in chapters 5 and 6. Although these two strains have similar blood pressure levels, the Dahl rats become progressively proteinuric as they age. The cause of early onset albuminuria in Dahl rats was previously found to be a polygenic trait.(79) In that study, genome-wide linkage, and quantitative trait loci (QTL) mapping analysis was performed. These QTLs were subsequently used to identify individual genes that are involved in the development of proteinuria. This was done by microarray analysis on purified Dahl and SHR glomeruli and comparing the differential regulation in time to the previously defined QTLs. Dynamin, which is discussed in chapter 5, was one of the cytoskeleton-related genes identified in this manner. TMEM14A was one of the most markedly downregulated genes in the comparison of relative expression prior to QTL correlation. Future perspectives In conclusion, the work presented in this thesis adds to the knowledge of the pathways to proteinuria by both challenging the previously held tenet of a static filtration barrier and supporting the theories entailing a dynamically regulated interplay between the various layers of the glomerular filtration barrier in conjunction with the tubular reabsorption apparatus. As also reviewed by Comper et al., the functionality of both the GFB and proximal tubular reabsorption seems to depend on whether proteinuric circumstances are present.(129) The expansion of comprehension of the pathophysiological mechanisms underlying pathways to proteinuria will be key to identifying new therapeutic targets. As described above, the novel zebrafish model of nephropathic cystinosis has already proven its worth for testing new therapeutic compounds whilst simultaneously offering new insights in the pathophysiology of cystinosis.
RkJQdWJsaXNoZXIy MTk4NDMw