Nedd4-2 ablation in kidney improves glycaemic control in diabetic mice.

Manning, JA; Jesudason, S; Moretti, PAB; Pitson, SM; Chou, ASY; Shabbar, M; Saad, S; Pollock, C; Kumar, S

Nedd4-2 ablation in kidney improves glycaemic control in diabetic mice.

Manning, JA Jesudason, S Moretti, PAB Pitson, SM Chou, ASY Shabbar, M Saad, S Pollock, C Kumar, S

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Cell Death Dis, 2025, 16, (1), pp. 496
Issue Date:: 2025-07-05

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Field	Value	Language
dc.contributor.author	Manning, JA
dc.contributor.author	Jesudason, S
dc.contributor.author	Moretti, PAB
dc.contributor.author	Pitson, SM
dc.contributor.author	Chou, ASY
dc.contributor.author	Shabbar, M
dc.contributor.author	Saad, S
dc.contributor.author	Pollock, C
dc.contributor.author	Kumar, S
dc.date.accessioned	2026-03-12T05:55:06Z
dc.date.available	2025-06-23
dc.date.available	2026-03-12T05:55:06Z
dc.date.issued	2025-07-05
dc.identifier.citation	Cell Death Dis, 2025, 16, (1), pp. 496
dc.identifier.issn	2041-4889
dc.identifier.issn	2041-4889
dc.identifier.uri	http://hdl.handle.net/10453/194308
dc.description.abstract	NEDD4-2, a ubiquitin ligase, regulates a number of ion channels and transporters by promoting their ubiquitination, internalisation and degradation, thereby affecting many signalling and physiological outcomes. Loss of this gene in mice results in tubular cell death and a chronic kidney disease (CKD)-like phenotype due to aberrant Na+ transport, caused by elevated expression of NEDD4-2 substrates including the epithelial sodium channel (ENaC). One of the biggest risk factors for CKD is diabetes, as up to 50% of diabetic patients develop diabetic kidney disease (DKD). Reduced levels of Nedd4-2 are associated with DKD in patients, therefore we investigated if this gene contributes to the development of this disease. In a diabetic (db/db) mouse model that develops DKD, we observed reduced expression of Nedd4-2 that correlated with disease progression. Substrates of NEDD4-2, including ENaC, were elevated in db/db mice, suggesting that NEDD4-2 dysfunction is involved in disease pathology. Intriguingly, genetic ablation of Nedd4-2 in this diabetic model did not exacerbate kidney disease severity beyond Nedd4-2 loss alone, but corrected metabolic parameters via a reduction of aldosterone levels, restoration of insulin signaling and reduced blood glucose levels. Hence, we conclude that a reduced Nedd4-2 level is detrimental for kidney health, however unexpectedly improves glycemic control in diabetes.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation.ispartof	Cell Death Dis
dc.relation.isbasedon	10.1038/s41419-025-07826-3
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1112 Oncology and Carcinogenesis
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Nedd4 Ubiquitin Protein Ligases
dc.subject.mesh	Mice
dc.subject.mesh	Epithelial Sodium Channels
dc.subject.mesh	Diabetic Nephropathies
dc.subject.mesh	Kidney
dc.subject.mesh	Diabetes Mellitus, Experimental
dc.subject.mesh	Glycemic Control
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Kidney
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Diabetic Nephropathies
dc.subject.mesh	Diabetes Mellitus, Experimental
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Male
dc.subject.mesh	Epithelial Sodium Channels
dc.subject.mesh	Nedd4 Ubiquitin Protein Ligases
dc.subject.mesh	Glycemic Control
dc.subject.mesh	Animals
dc.subject.mesh	Nedd4 Ubiquitin Protein Ligases
dc.subject.mesh	Mice
dc.subject.mesh	Epithelial Sodium Channels
dc.subject.mesh	Diabetic Nephropathies
dc.subject.mesh	Kidney
dc.subject.mesh	Diabetes Mellitus, Experimental
dc.subject.mesh	Glycemic Control
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Mice, Knockout
dc.title	Nedd4-2 ablation in kidney improves glycaemic control in diabetic mice.
dc.type	Journal Article
utslib.citation.volume	16
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2026-03-12T05:54:59Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	16
utslib.citation.issue	1

Abstract:

NEDD4-2, a ubiquitin ligase, regulates a number of ion channels and transporters by promoting their ubiquitination, internalisation and degradation, thereby affecting many signalling and physiological outcomes. Loss of this gene in mice results in tubular cell death and a chronic kidney disease (CKD)-like phenotype due to aberrant Na+ transport, caused by elevated expression of NEDD4-2 substrates including the epithelial sodium channel (ENaC). One of the biggest risk factors for CKD is diabetes, as up to 50% of diabetic patients develop diabetic kidney disease (DKD). Reduced levels of Nedd4-2 are associated with DKD in patients, therefore we investigated if this gene contributes to the development of this disease. In a diabetic (db/db) mouse model that develops DKD, we observed reduced expression of Nedd4-2 that correlated with disease progression. Substrates of NEDD4-2, including ENaC, were elevated in db/db mice, suggesting that NEDD4-2 dysfunction is involved in disease pathology. Intriguingly, genetic ablation of Nedd4-2 in this diabetic model did not exacerbate kidney disease severity beyond Nedd4-2 loss alone, but corrected metabolic parameters via a reduction of aldosterone levels, restoration of insulin signaling and reduced blood glucose levels. Hence, we conclude that a reduced Nedd4-2 level is detrimental for kidney health, however unexpectedly improves glycemic control in diabetes.

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http://hdl.handle.net/10453/194308