Transmembrane Protein 14A protects glomerular filtration barrier integrity 105 6 Introduction Proteinuria is an important risk factor for progression of renal disease and cardiovascular mortality (2). Proteinuria occurs when glomerular filtration barrier (GFB) integrity is compromised. The GFB consists of fenestrated endothelial cells lined with glycocalyx, the glomerular basement membrane, and podocyte foot processes. Understanding the pathophysiology and mechanisms leading to proteinuria is essential in the quest to understanding nephron function and finding new potential therapeutic targets for proteinuric renal diseases. To study the pathophysiology and underlying mechanisms of the development of proteinuria, we have further analyzed spontaneously proteinuric Dahl salt sensitive rats (Dahl) (79, 90-93). Analysis of differentially regulated glomerular mRNA yielded various genes potentially involved in the development of proteinuria.(17, 93) One of the noteworthy downregulated genes in the Dahl rat, was transmembrane protein 14A (Tmem14a). TMEM14A is 99 amino acid integral membrane protein with three transmembrane domains. Its structure has been identified by nuclear magnetic resonance spectroscopy (94). Relatively little is known of its function. It has been described to be involved in preventing apoptosis by preventing loss of mitochondrial membrane potential through Bax suppression in an in vitro study (95). However, its function in maintenance of GFB integrity has not yet been described. Interestingly, Apoptosis of podocytes has been described as a pathophysiological process in proteinuric renal disease, especially diabetic nephropathy, in various experimental models (96-100). Moreover, podocyte detachment and loss has been suggested to been dependent on apoptotic caspases in an experimental animal model.(101) As Tmem14a was found to be downregulated in rats with a proteinuric phenotype in the Dahl array, we hypothesize that it is required for maintaining GFB integrity and that is also differentially expressed in human proteinuric disease. Materials and Methods Microarray Microarray data containing information on differentially regulated genes in glomeruli obtained from spontaneously proteinuric Dahl salt sensitive (Dahl) male rats strain and non-proteinuric spontaneous hypertensive (SHR) male rats at 4 and 6 weeks of age was used to identify genes potentially involved in the development of proteinuria. The
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