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• W1602190038 abstract "The ability of the kidney to retain plasma protein relies on a functional glomerular filtration barrier, consisting of endothelial cells, the glomerular basement membrane (GBM) and podocytes. Damage to the glomerular filter is clinically detected as proteinuria, which also is an independent predictor of the progression kidney disease (Ruggenenti et al. 2001). Within the last decades, the importance of podocytes for a functional glomerular filtration barrier has emerged. Podocytes are terminally differentiated epithelial cells with a highly organized structure, and injury to the podocyte structure appears to be a common finding in acquired proteinuric conditions (Pavenstadt et al. 2003). Identification of genes that are involved in physiological and pathophysiological functions of the podocytes is a major task. Recent studies indicate that bestrophin-3 (Best3) has cell protective functions in a number of cell types (Lee et al. 2012, Jiang et al. 2013, Song et al. 2014). In the present issue of Acta Physiologica, Golubinskaya et al. use cultured podocytes, kidneys and isolated glomeruli of the mouse kidney to provide a thorough characterization of Best3 expression under normal conditions and in response to injury induced by endoplasmaic reticulum (ER) stress (Golubinskaya et al. 2015). Their report shed light on the complex regulation of Best3 in podocytes and will help pave the way for future studies on the pathogenesis of kidney diseases with podocyte injury. The human bestrophin gene family consist of four members: Best1 (also named VMD2), Best2 (VMD2L1), Best3 (VMD2L3) and Best4 (VMD2L2). In the mouse, however, Best4 is considered a pseudogene (Kramer et al. 2004). Best1 and Best2 have been proposed to function as anion channels (Duran et al. 2010). Although Best3 mRNA is ubiquitously expressed (Kramer et al. 2004), Best3 only appears to function as a channel in vascular smooth muscle cells and cardiomyocytes (Matchkov et al. 2008, O'Driscoll et al. 2008). To make matters more complicated, Best3 mRNA is not just Best3 mRNA. Full-length Best3 mRNA has only been detected in the heart, whereas different splice variants exist in a number of tissues (Kramer et al. 2004). The alternative splicing of the Best3 can remove exons 2, 3 and 6 (Kramer et al. 2004, Srivastava et al. 2008). The full-length Best3 mRNA was not detected in podocytes, but two splice variants, a short variant lacing exons 2,3 and 6 (−2,-3-6) and a longer form lacking exons 2 and 3 (−2,−3,+6), were expressed (Golubinskaya et al. 2015). At the protein level, Best3 was detected by Western blotting in heart, in kidney cortex and in cultured podocytes (Golubinskaya et al. 2015). Although the splice variants are predicted to produce truncated forms of Best3 protein without channel properties (Kramer et al. 2004, Srivastava et al. 2008), Golubinskaya et al. found that Best3 had a higher molecular weight in podocytes and kidney cortex than in hearts (Golubinskaya et al. 2015). The discrepancy between the predicted and observed proteins weights in the different tissues could be due to post-translational modifications of Best3, but further studies are needed to clarify the underlying mechanism. In cultured proximal tubular cells, Best3 levels are increased during ER stress and were shown to enhance cell survival through suppression of the ER stress marker C/EBP homologous protein (CHOP) (Lee et al. 2012). A similar mechanism could be envisioned for Best3 in podocytes. Exogenous agents were used to induce ER stress in the podocytes both in vitro and in vivo (Golubinskaya et al. 2015). Intriguingly, the two splice variants differed in their response to ER stress. In agreement with results from the cultured proximal tubular cells (Lee et al. 2012), the total level of Best3 mRNA was increased in response to ER stress in podocytes (Golubinskaya et al. 2015). However, Golubinskaya et al. showed that the temporal expression profile of the short splice variant correlated with the CHOP expression profile in podocytes, while the expression profile of the longer splice variant correlated with nestin mRNA (Golubinskaya et al. 2015). Nestin is an intermediate filament suggested to have a role in regulation of the cytoskeletal structure (Herrmann & Aebi 2000). Nestin is expressed in differentiated podocytes of the adult kidney (Chen et al. 2006) and has been demonstrated to have a protective role against injury in cultured podocytes (Liu et al. 2012). Best3 protein was found to be colocalized with nestin in podocytes, and together with the similar mRNA expression profile of the long variant of Best3 and nestin, it led the authors to speculate that they are functionally connected (Golubinskaya et al. 2015). It should be noted, however, that the anti-Best3 antibody used in the report (Golubinskaya et al. 2015) was not able to discriminate between the splice variants of Best3, and splice variant-specific antibodies will be needed to demonstrate whether the protein products of the two Best3 splice variants are differentially localized in podocytes. Golubinskaya et al. (Golubinskaya et al. 2015) provide a number of interesting observations, and the report indicates that the Best3 splice variants could potentially have different physiological functions. The data are, however, correlative, and detailed molecular intervention studies will be needed to elucidate the individual roles of Best3 splice variants for the function of podocytes. This will not be an easy task, but could provide an important step for the understanding of kidney diseases with podocyte injury. None." @default.
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• W1602190038 date "2015-06-16" @default.
• W1602190038 modified "2023-09-26" @default.
• W1602190038 title "Stressed podocytes - Bestrophin-3 is not just Bestrophin-3" @default.
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• W1602190038 doi "https://doi.org/10.1111/apha.12539" @default.
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