Abstract-Although the biophysical fingerprints (ion selectivity, voltage-dependence, kinetics, etc) of Ca 2ϩ -activated Cl Ϫ currents are well established, their molecular identity is still controversial. Several molecular candidates have been suggested; however, none of them has been fully accepted. We have recently characterized a cGMP-dependent Ca 2ϩ -activated Cl Ϫ current with unique characteristics in smooth muscle cells. This novel current has been shown to coexist with a "classic" (cGMP-independent) Ca 2ϩ -activated Cl Ϫ current and to have characteristics distinct from those previously known for Ca 2ϩ -activated Cl Ϫ currents. Here, we suggest that a bestrophin, a product of the Best gene family, is responsible for the cGMP-dependent Ca 2ϩ -activated Cl Ϫ current based on similarities between the membrane currents produced by heterologous expressions of bestrophins and the cGMP-dependent Ca 2ϩ -activated Cl Ϫ current. This is supported by similarities in the distribution pattern of the cGMP-dependent Ca 2ϩ -activated Cl Ϫ current and bestrophin-3 (the product of Best-3 gene) expression in different smooth muscle. Furthermore, downregulation of Best-3 gene expression with small interfering RNA both in cultured cells and in vascular smooth muscle cells in vivo was associated with a significant reduction of the cGMP-dependent Ca 2ϩ -activated Cl Ϫ current, whereas the magnitude of the classic Ca 2ϩ -activated Cl Ϫ current was not affected. Ϫ channel, which results in depolarization in vascular smooth muscle. Furthermore, the current is of similar magnitude as "classic" Ca 2ϩ -activated Cl Ϫ currents in most vascular beds and even larger in some vascular smooth muscles. 3 It is, therefore, highly desirable to know the molecular structure of the channel responsible for this current because it is likely to play an important role in smooth muscle function.Although their biophysical fingerprints (ion selectivity, voltage-dependence, kinetics, etc) are well established, 4 -6 the molecular identity of Ca 2ϩ -sensitive Cl Ϫ channels is still controversial. 7 Recently, the gene responsible for vitelliform macular dystrophy 8 and its homologs that code for bestrophin proteins have been suggested as candidates. 9,10 Four bestrophin family members in the mammalian genome and many homologues in genomes of invertebrates and even prokaryotes have been identified. 11-13 Two different nomenclatures for mammalian bestrophins were previously devel- The majority of suggestions that bestrophins function as Cl Ϫ channels are based on the findings that expression of the gene in different cell types leads to the appearance of a Cl Ϫ conductance 9,10 and that mutations or chemical modifications of the predicted channel pore change this conductance. [15][16][17][18] Although downregulation by small interfering (si)RNA in recent studies demonstrated a direct association between the endogenous Cl Ϫ current in epithelial cell culture and Best-1 expression, 19 -21 the exact role of the bestrophins in native tissues remains questionable...
NLRX1 is a mitochondrial innate immune receptor involved in viral immunity. Stokman et al. found that loss of NLRX1 increased cellular mitochondrial activity, production of reactive oxygen species, and apoptosis during oxidative stress in kidney injury.
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Animal models are essential tools for designing new strategies to prevent DN. C57Bl/6 (B6) mice are widely used for transgenic mouse models, but are relatively resistant to DN. This study aims to identify the most effective method to induce DN in a type 1 (T1D) and a type 2 diabetes (T2D) model in B6 mice. For T1D-induced DN, mice were fed a control diet, and randomised to streptozotocin (STZ) alone, STZ+unilateral nephrectomy (UNx), or vehicle/sham. For T2D-induced DN, mice were fed a western (high fat) diet, and randomised to either STZ alone, STZ+UNx, UNx alone, or vehicle/sham. Mice subjected to a control diet with STZ +UNx developed albuminuria, glomerular lesions, thickening of the glomerular basement membrane, and tubular injury. Mice on control diet and STZ developed only mild renal lesions. Furthermore, kidneys from mice on a western diet were hardly affected by diabetes, UNx or the combination. We conclude that STZ combined with UNx is the most effective model to induce T1D-induced DN in B6 mice. In our hands, combining western diet and STZ treatment with or without UNx did not result in a T2D-induced DN model in B6 mice.
Visualization of the subcellular localization of SARS-CoV-2 proteins in lung patient material of COVID-19 patients is important for the understanding of this new virus. We detected viral proteins in the context of the ultrastructure of infected cells and tissues and discovered that some viral proteins accumulate in novel, lipid-filled compartments.
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