Transmembrane Protein 14A protects glomerular filtration barrier integrity 115 6 The specific function of the TMEM14A protein is not yet fully understood. As stated before, it has been associated with preventing Bax-mediated apoptosis (95). Apoptosis was previously deemed to not be a significant cause of podocyte loss in most proteinuric diseases (103). However, recent experiments by Yamamoto et al. show that loss of podocytes seems to be initiated by the start of the apoptotic process by caspase 3 (101). Apoptosis pathways have previously been implicated as one of the pathophysiological mechanisms in the development of diabetic nephropathy and can be attenuated by ACE or ARBII inhibition (96, 99). As no increase in glomerular TMEM14A protein expressing surface area was seen in diabetic nephropathy glomeruli, insufficient prevention of apoptosis due to a pre-existent relative lack or impairment of TMEM14A might be a factor in the development of proteinuria in these patients. This would be in line with recent results from other studies suggesting that induction of apoptosis causes podocyte detachment (101). Interestingly, previous studies show that Dahl rats indeed have a lower number of podocytes compared to SHR (17). The difference in TMEM14A expression between DN and other investigated proteinuric renal disease warrants further exploration, specifically into TMEM14A and apoptosis in diabetic nephropathy models. The main limitation of this study is that is largely descriptive in nature, where the exact function of TMEM14A is not yet known. Additionally, external factors influencing its potential expression, degradation and activation are not yet known and as such not yet investigated. Also, although the use of various experimental models and species in this study is one of its strengths, it also provides a potential limitation due to interspecies variability, which might lead to an incomplete or incorrect analysis and extrapolation of results. As TMEM14A has strong homology across species, it could very well be an evolutionary well-conserved gene that is part of a biological mechanism with broader involvement than the nephron alone. Future studies are needed to further elucidate the exact role and surrounding mechanisms of TMEM14A in nephron function. In particular, interactions with other proteins involved in maintaining GFB integrity are yet to be unravelled. Moreover, the effect of knocking down TMEM14A through morpholino injection could be due to off-target effect of morpholino injection.(104) The used anti-TMEM14A antibody did not provide reliable assessment of TMEM14A expression in zebrafish and as such, it is possible that the observed proteinuria is an off-target effect. It has been suggested in literature to validate observed morpholino induced phenotypes in embryos bearing mutations in the respective gene. The generation of a TMEM14A mutant would not only establish whether
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