Abstract
Alpha-adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na+,K+-ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na+,K+-ATPase activity, and their Na+,K+-ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na+,K+-ATPase because of adaptin-mu2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na+,K+-ATPase activity, mu2-subunit hyperphosphorylation, and impaired Na+,K+-ATPase endocytosis. Thus, increased renal Na+,K+-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na+,K+-ATPase endocytosis in response to natriuretic signals.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Protein Complex 2 / chemistry
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Adaptor Protein Complex 2 / metabolism*
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Adaptor Protein Complex mu Subunits / chemistry
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Adaptor Protein Complex mu Subunits / metabolism*
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Amino Acid Substitution
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Animals
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Blood Pressure / genetics
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Blood Pressure / physiology
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Cell Line / drug effects
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Cell Line / enzymology
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / physiology*
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Dopamine / pharmacology
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Endocytosis / drug effects
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Endosomes / enzymology
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Epithelium / enzymology
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Humans
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Hypertension / enzymology
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Hypertension / genetics*
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Hypertension / physiopathology
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Kidney Tubules / drug effects
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Kidney Tubules / enzymology*
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Microfilament Proteins / genetics
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Microfilament Proteins / physiology*
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Mutagenesis, Site-Directed
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Natriuresis / drug effects
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Natriuresis / genetics
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Natriuresis / physiology*
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Opossums
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Phosphoprotein Phosphatases / metabolism
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Protein Interaction Mapping
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Protein Subunits
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Rats
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Rats, Mutant Strains
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Recombinant Fusion Proteins / physiology
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Sodium-Potassium-Exchanging ATPase / metabolism*
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Structure-Activity Relationship
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Transfection
Substances
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ADD2 protein, human
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Adaptor Protein Complex 2
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Adaptor Protein Complex mu Subunits
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Add2 protein, rat
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Cytoskeletal Proteins
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Microfilament Proteins
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Protein Subunits
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Recombinant Fusion Proteins
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adaptor protein complex 2, mu 2 subunit
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Phosphoprotein Phosphatases
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Atp1a2 protein, rat
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Sodium-Potassium-Exchanging ATPase
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Dopamine