Chapter 1 12 sodium. The first part of ultrafiltrate is isotonic to serum, and as such, active processes are required to reabsorb these solutes. Hence, the proximal tubule epithelial cells possess many mitochondria to facilitate these active processes. On the tubular luminal side, these cells are lined with microvilli which form the brush border, which significantly increases the luminal surface area. It is here that solutes and colloids are reabsorbed. Some groups have provided evidence that albumin does in fact pass the glomerular filtration barrier in much greater quantities than previously thought. They claim that tubular reabsorption mechanisms thus play a larger role in preventing proteinuria than has been attributed to them before.(15) Although the relative contribution to preventing proteinuria is controversial, there is a general consensus that adequate tubular reabsorption mechanisms are required to prevent, at least in part, the loss of protein in the urine. A complete loss of tubular reabsorption function results in Fanconi syndrome. This syndrome is characterized by proteinuria and severe acid-base and electrolyte disorders. In children, the most common cause of Fanconi syndrome is nephropathic cystinosis. Nephropathic cystinosis is a lysosomal storage disorder that results in cystine crystal deposition in various tissues. The proximal tubule is usually the first affected site. As stated above, pathological processes in any one of the GFB layers can lead to proteinuria. Although this has long been attributed to the individually affected layer, it is now deemed more likely that the glomerular filtration barrier functions as a whole unit and requires all components to properly function. Moreover, the GFB can be seen as a dynamic barrier with various repair and compensation mechanisms rather than a static barrier that only sieves particles based on size, weight, and hydrostatic pressure. Identifying new targets Identifying which components of the glomerular filtration barrier are needed to maintain proper barrier function is essential to identifying potential therapeutic options. Historically, the function of the various components of the glomerular filtration barrier has been discovered in patients with genetic defects leading to proteinuria.(16) More recently, experimental animal models have been used to identify genes and their encoded products that might be important in GFB function. For example, genetic association studies in proteinuric rats have identified a panel of various genes potentially involved in the development of proteinuria.(17) After identifying these genes in a previously described array, the candidate genes and their encoded proteins were then investigated further to establish whether a direct relation to the development of proteinuria is present. In multiple studies presented here, the method to examine whether a protein has a significant role in the development of proteinuria consisted of assessing whether knocking down mRNA
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