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      Dietary sodium modulates nephropathy in Nedd4-2-deficient mice

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          Abstract

          Salt homeostasis is maintained by tight control of Na + filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na + channel (ENaC), which is rate-limiting for Na + reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high dietary Na + exacerbated kidney injury in Nedd4-2-deficient mice, significantly perturbing normal postnatal nephrogenesis and resulting in multifocal areas of renal dysplasia, increased markers of kidney injury and a decline in renal function. In control mice, high dietary Na + resulted in reduced levels of ENaC. However, Nedd4-2-deficient kidneys maintained elevated ENaC even after high dietary Na +, suggesting that the inability to efficiently downregulate ENaC is responsible for the salt-sensitivity of disease. Importantly, low dietary Na + significantly ameliorated nephropathy in Nedd4-2-deficient mice. Our results demonstrate that due to dysregulation of ENaC, kidney injury in Nedd4-2-deficient mice is sensitive to dietary Na +, which may have implications in the management of disease in patients with kidney disease.

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          The single-cell transcriptomic landscape of early human diabetic nephropathy

          Significance Single-nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.
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            Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.

            Aldosterone stimulates sodium transport in the renal collecting duct by activating the epithelial sodium channel (ENaC). To investigate the basis of this effect, we have developed a novel set of rabbit polyclonal antibodies to the 3 subunits of ENaC and have determined the abundance and distribution of ENaC subunits in the principal cells of the rat renal collecting duct. Elevated circulating aldosterone (due to either dietary NaCl restriction or aldosterone infusion) markedly increased the abundance of alphaENaC protein without increasing the abundance of the beta and gamma subunits. Thus, alphaENaC is selectively induced by aldosterone. In addition, immunofluorescence immunolocalization showed a striking redistribution in ENaC labeling to the apical region of the collecting duct principal cells. Finally, aldosterone induced a shift in molecular weight of gammaENaC from 85 kDa to 70 kDa, consistent with physiological proteolytic clipping of the extracellular loop as postulated previously. Thus, at the protein level, the response of ENaC to aldosterone stimulation is heterogenous, with both quantitative and qualitative changes that can explain observed increases in ENaC-mediated sodium transport.
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              Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome

              In its early stages, symptoms of chronic kidney disease (CKD) are usually not apparent. Significant reduction of the kidney function is the first obvious sign of disease. If diagnosed early (stages 1 to 3), the progression of CKD can be altered and complications reduced. In stages 4 and 5 extensive kidney damage is observed, which usually results in end-stage renal failure. Currently, the diagnosis of CKD is made usually on the levels of blood urea and serum creatinine (sCr), however, sCr has been shown to be lacking high predictive value. Due to the development of genomics, epigenetics, transcriptomics, proteomics, and metabolomics, the introduction of novel techniques will allow for the identification of novel biomarkers in renal diseases. This review presents some new possible biomarkers in the diagnosis of CKD and in the prediction of outcome, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), uromodulin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), miRNA, ncRNA, and lincRNA biomarkers and proteomic and metabolomic biomarkers. Complicated pathomechanisms of CKD development and progression require not a single marker but their combination in order to mirror all types of alterations occurring in the course of this disease. It seems that in the not so distant future, conventional markers may be exchanged for new ones, however, confirmation of their efficacy, sensitivity and specificity as well as the reduction of analysis costs are required.
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                Author and article information

                Contributors
                Jantina.manning@unisa.edu.au
                sharad.kumar@unisa.edu.au
                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group UK (London )
                1350-9047
                1476-5403
                4 December 2019
                4 December 2019
                June 2020
                : 27
                : 6
                : 1832-1843
                Affiliations
                [1 ]ISNI 0000 0000 8994 5086, GRID grid.1026.5, Centre for Cancer Biology, , University of South Australia and SA Pathology, ; Adelaide, SA 5001 Australia
                [2 ]ISNI 0000 0004 1936 7304, GRID grid.1010.0, Faculty of Medicine, , University of Adelaide, ; Adelaide, SA 5005 Australia
                [3 ]ISNI 0000 0001 2294 430X, GRID grid.414733.6, SA Pathology, ; Frome Road, Adelaide, SA 5000 Australia
                Article
                468
                10.1038/s41418-019-0468-5
                7244563
                31802037
                b6afeda6-4381-40f3-93d6-2cd7644e4ea7
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 September 2019
                : 20 November 2019
                : 21 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Award ID: GNT1103006 & GNT1099307
                Award Recipient :
                Categories
                Article
                Custom metadata
                © ADMC Associazione Differenziamento e Morte Cellulare 2020

                Cell biology
                ubiquitin ligases,kidney diseases
                Cell biology
                ubiquitin ligases, kidney diseases

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