Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/110873
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Type: | Journal article |
Title: | Deletion of Nedd4-2 results in progressive kidney disease in mice |
Author: | Henshall, T. Manning, J. Alfassy, O. Goel, P. Boase, N. Kawabe, H. Kumar, S. |
Citation: | Cell Death and Differentiation, 2017; 24(12):2150-2160 |
Publisher: | Nature Publishing Group |
Issue Date: | 2017 |
ISSN: | 1350-9047 1476-5403 |
Statement of Responsibility: | Tanya L Henshall, Jantina A Manning, Omri S Alfassy, Pranay Goel, Natasha A Boase, Hiroshi Kawabe and Sharad Kumar |
Abstract: | NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na⁺ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na⁺Cl⁻ cotransporter expression, increased Na⁺ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na⁺ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na⁺-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4-2 and that Nedd4-2 deletion is associated with hypertension on a normal Na⁺ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology. |
Keywords: | Animals Mice, Transgenic Mice Kidney Diseases Amiloride Male Epithelial Sodium Channels Epithelial Sodium Channel Blockers Nedd4 Ubiquitin Protein Ligases |
Rights: | © The Author(s) 2017 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
DOI: | 10.1038/cdd.2017.137 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1103006 http://purl.org/au-research/grants/nhmrc/1020755 http://purl.org/au-research/grants/nhmrc/1099307 |
Published version: | http://dx.doi.org/10.1038/cdd.2017.137 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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hdl_110873.pdf | Published Version | 3.25 MB | Adobe PDF | View/Open |
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