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• W2595380400 abstract "Adaptation of the organism to potassium (K + ) deficiency requires precise coordination among organs involved in K + homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K + retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na + /Cl − cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K + restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 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 excessive K + wasting. Moreover, K + restriction increased WNK1 and WNK4 expression 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." @default.
• W2595380400 created "2017-03-23" @default.
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• W2595380400 date "2017-03-13" @default.
• W2595380400 modified "2023-10-17" @default.
• W2595380400 title "Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion" @default.
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• W2595380400 doi "https://doi.org/10.1681/asn.2016070732" @default.
• W2595380400 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5533229" @default.
• W2595380400 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28289184" @default.
• W2595380400 hasPublicationYear "2017" @default.
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