Pathophysiological consequences of changes in the coupling ratio of Na,K-ATPase for renal sodium reabsorption and its implications for hypertension.
Recent reports indicate that alpha 1-Na,K-ATPase from Dahl salt-sensitive (DS) rats contains a glutamine for leucine substitution associated with increased Na-K coupling at unchanged maximal velocity. Genetic analyses suggest that alpha 1-Na,K-ATPase is a potential hypertension gene. Therefore, we investigated whether renal Na+ metabolism could constitute a pathophysiological link between the molecular/functional change in Na,K-ATPase and hypertension. We simulated the consequences of increased Na-K coupling on overall Na-bicarbonate reabsorption in a proximal tubular transport model that incorporates apical Na-H exchanger and basolateral Na-bicarbonate cotransporter, K+ channel, and Na,K-ATPase. As expected, increases in the levels of the former three transport pathways yielded higher Na+ reabsorption. In contrast, increases in the maximal velocity of the Na,K-ATPase with a normal 3:2 (Na-K) coupling ratio did not increase Na+ reabsorption when apical Na-H exchange activity was limiting overall absorption. However, an increase in the Na-K coupling from 3:2 to 3:1, reported for the mutant alpha 1-Na,K-ATPase in DS rats, was associated with greater Na+ reabsorption. This increase is a consequence of lower cytosolic pH and secondary stimulation of the Na-H exchanger at its allosteric H+ site. Decreased pH results from activation of Na-bicarbonate cotransport by Na,K-ATPase-dependent membrane hyperpolarization due to greater charge movement in 3:1 Na-K coupling. Thus, an increase in the Na-K coupling ratio results in an altered set point for cellular Na+ metabolism, with higher sodium reabsorption at unchanged Na,K-ATPase levels. The simulations thereby lend support for a unifying explanation for the salt sensitivity of DS rats, which has been proposed to stem from a mutation in the alpha 1-Na,K-ATPase.
Orosz
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Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4970, USA.
Hopfer
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D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000502:physiology / Q000503:physiopathology*; D007700:Kinetics; D008433:Mathematics; D008955:Models, Cardiovascular; D051381:Rats; D011922:Rats, Mutant Strains; D012964:Sodium / Q000378:metabolism*; D027982:Sodium-Bicarbonate Symporters; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D001639:Bicarbonates; D002352:Carrier Proteins; D027982:Sodium-Bicarbonate Symporters; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium