Adducin and hypertension.
Adducin is a heterodimeric cytoskeleton protein consisting of an alpha-subunit and either a beta- or gamma-subunit. In rats and humans, mutation of the alpha-adducin subunit leads to the stimulation of the sodium (Na(+)), potassium (K(+))-adenosine triphosphate (ATP)-ase activity in renal tubular cells, increased renal Na(+) reabsorption, and, subsequently, hypertension. Ouabain is a hormone that is released by the hypothalamus and, possibly, the adrenal glands. In renal tubular cells it modulates Na(+)/K(+)-ATPase activity and regulates natriuresis. Plasma ouabain levels increase with the number of copies of the mutated alpha-adducin allele. Rostafuroxin is a digitoxygenin derivative that selectively displaces ouabain from the Na(+)/K(+)-ATPase receptor and lowers blood pressure in rats and humans. In this short editorial review, we summarize the recent experimental, clinical and epidemiological evidence that contributed to our understanding of the pathogenetic mechanisms that lead to hypertension associated with the alpha-adducin Gly460Trp polymorphism and its interaction with ouabain. We propose that a pharmacogenomic approach, as applied in an ongoing Phase II dosage study of rostafuroxin, will be a critical step in moving the adducin hypothesis from experimental and observational studies to clinical application.
Staessen
Jan A
JA
University of Leuven, Study Coordinating Centre, Laboratory of Hypertension, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. jan.staessen@med.kuleuven.be
Bianchi
Giuseppe
G
D000483:Alleles; D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005544:Forecasting; D006579:Heterozygote; D006801:Humans; D006977:Hypertension, Renal / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology; D009154:Mutation; D009318:Natriuresis / Q000187:drug effects / Q000235:genetics; D010042:Ouabain / Q000378:metabolism / Q000494:pharmacology; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000235:genetics; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D000099291:Adducins
D000732:Androstanols; D002148:Calmodulin-Binding Proteins; D010042:Ouabain; D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase; D000099291:Adducins; C106263:rostafuroxin