Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0235394 (
wasting
)
8,040
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 (
Nedd4L
Pax8/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
Nedd4L
Pax8/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
Nedd4L
Pax8/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.
...
PMID:Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion. 2828 84
