Proteomics and tubulopathies

Abstract

In the last thirty decade, with the emergence of new trends in molecular biology and advances in high-throughput technologies, much progress has been made in basic renal physiology. Molecular genetics has allowed the identification and elucidation of the structure, function and effects of the mutations of several of the main transporters and ion channels involved in renal disorders. Some renal stone disorders, such as cystinuria and Dent's disease, have been found to be due to mutations in genes SLC3A1 (type I) (See the section "Molecular biology and genotype-phenotype correlation in tubular dysfunction") and SLC7A9 (type II and type III), (See the section "Molecular biology and genotype-phenotype correlation in tubular dysfunction") and in CLC5, respectively. Liddle syndrome, a rare cause of hypertension, is now known to be caused by a mutation in tubular transport, due to a mutation in the SCNN1B gene, encoding for a Na+ channel protein (ENaC). Nevertheless, numerous issues remain unsettled and warrant additional research. These important advances and discoveries are not without limitations and challenges as changes in individual gene expression do not always translate into changes in its protein or protein modification. This raises proteomics as the most logical next step in our understanding of biological processes, as proteins from these deregulated genes are the functional agents in the cells. Proteomics takes a global and comprehensive view of a system, involving in many cases some notion of high throughput; but in contrast to genomics, there is no single biochemical method that can be used for the analysis of all proteins. Genomics and proteomics can complement each other in clinical applications by balancing the strengths and weaknesses of each individual technology. Several proteomics approaches have been exploited to shed more light on the molecular pathophysiology of several hereditary tubular disorders, such as Fanconi and Gitelman syndromes, and have provided important insights into the defective molecular mechanisms underlying these tubulopathies. Here we summarize several of the most important discoveries arising from molecular genetic and proteomic studies on hereditary tubular dysfunctions and show how these results can complement each other to increase our comprehension of these disorders at the molecular level.