Renal tubular ubiquitin-protein ligase NEDD4-2 is required for renal adaptation during long-term potassium depletion

Lama Al-Qusairi, Denis Basquin, Ankita Roy, Renuga Devi Rajaram, Marc P. Maillard, Arohan R. Subramanya, Olivier Staub

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Adaptation of the organism to potassium (K+) deficiency requires precise coordination among organs involved in K+ homeostasis, includingmuscle, liver, andkidney.Howthe latterperforms functional andmolecular changes toensure K+ retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodiumchannel (ENaC),Na+/Cl-cotransporter (NCC), and with no-lysine-kinase 1 (WNK1).After dietaryK+ restriction for 2weeks, compared with control littermates, inducible renal tubularNEDD4-2 knockout (Nedd4LPax8/LC1) mice exhibited severe hypokalemia and urinary K+ wasting. Notably, expression of the ROMK K+ channel did not change in the distal convoluted tubule and decreased slightly in the cortical/medullary collecting duct, whereas BK channel abundance increased in principal cells of the connecting tubule/collecting ducts. However, K+ restriction also enhanced ENaC expression in Nedd4LPax8/LC1 mice, and treatment with the ENaC inhibitor, benzamil, reversed excessiveK+wasting. Moreover, K+ restriction increasedWNK1andWNK4expression and enhanced SPAK-mediated NCC phosphorylation in Nedd4LPax8/LC1 mice, with no change in total NCC.We propose a mechanism in which NEDD4-2 deficiency exacerbates hypokalemia during dietary K+ restriction primarily through direct upregulation of ENaC, whereas increased BK channel expression has a less significant role. These changes outweigh the compensatory antikaliuretic effects of diminished ROMK expression, increased NCC phosphorylation, and enhanced WNK pathway activity in the distal convoluted tubule. Thus,NEDD4-2 has a crucial role in K+ conservation through direct and indirect effects on ENaC, distal nephron K+ channels, and WNK signaling resolution.

Original languageEnglish (US)
Pages (from-to)2431-2442
Number of pages12
JournalJournal of the American Society of Nephrology
Issue number8
StatePublished - Aug 2017
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology


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