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.
© 2025. The Author(s).