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Type: Journal article
Title: The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease
Author: Manning, J.A.
Shah, S.S.
Nikolic, A.
Henshall, T.L.
Khew-Goodall, Y.
Kumar, S.
Citation: Cell Death and Disease, 2021; 12(4):398-1-398-16
Publisher: Nature Publishing Group
Issue Date: 2021
ISSN: 2041-4889
Statement of
Jantina A. Manning, Sonia S. Shah, Andrej Nikolic, Tanya L. Henshall, Yeesim Khew-Goodall and Sharad Kumar
Abstract: Kidney disease progression can be affected by Na+ abundance. A key regulator of Na+ homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na+ transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na+ induced damage remain poorly understood. Here we show that a high Na+ diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na+ rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/ β-catenin/TGF-β signaling in progressive kidney disease
Keywords: Animals
Mice, Transgenic
Xenopus laevis
Kidney Failure, Chronic
Ubiquitin-Protein Ligases
Xenopus Proteins
Endosomal Sorting Complexes Required for Transport
Nedd4 Ubiquitin Protein Ligases
Rights: © The Author(s) 2021 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
DOI: 10.1038/s41419-021-03688-7
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Appears in Collections:Aurora harvest 8
Environment Institute publications

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