Evidence for an interaction between adducin and Na⁺-K⁺-ATPase: relation to genetic hypertension

Abstract

Adducin point mutations are associated with genetic hypertension in Milan hypertensive strain (MHS) rats and in humans. In transfected cells, adducin affects actin cytoskeleton organization and increases the Na(+)-K(+)-pump rate. The present study has investigated whether rat and human adducin polymorphisms differently modulate rat renal Na(+)-K(+)-ATPase in vitro. We report the following. 1) Both rat and human adducins stimulate Na(+)-K(+)-ATPase activity, with apparent affinity in tens of nanomolar concentrations. 2) MHS and Milan normotensive strain (MNS) adducins raise the apparent ATP affinity for Na(+)-K(+)-ATPase. 3) The mechanism of action of adducin appears to involve a selective acceleration of the rate of the conformational change E(2) (K) --> E(1) (Na) or E(2)(K). ATP --> E(1)Na. ATP. 4) Apparent affinities for mutant rat and human adducins are significantly higher than those for wild types. 5) Recombinant human alpha- and beta-adducins stimulate Na(+)-K(+)-ATPase activity, as do the COOH-terminal tails, and the mutant proteins display higher affinities than the wild types. 6) The cytoskeletal protein ankyrin, which is known to bind to Na(+)-K(+)-ATPase, also stimulates enzyme activity, whereas BSA is without effect; the effects of adducin and ankyrin when acting together are not additive. 7) Pig kidney medulla microsomes appear to contain endogenous adducin; in contrast with purified pig kidney Na(+)-K(+)-ATPase, which does not contain adducin, added adducin stimulates the Na(+)-K(+)-ATPase activity of microsomes only about one-half as much as that of purified Na(+)-K(+)-ATPase. Our findings strongly imply the existence of a direct and specific interaction between adducin and Na(+)-K(+)-ATPase in vitro and also suggest the possibility of such an interaction in intact renal membranes.

Genetics of arterial hypertension and hypotension

“…the dopamine or Ang II receptor as shown in this report (Efendiev et al 2004). It remains open how these mechanisms that affect the dynamics of Na + /K + membrane expression are in accordance with results from another study suggesting that the kinetic activity of the Na + /K + ATPase is increased and its ATP affinity is higher in the presence of the rat 316Y and the human 460W variants compared to wildtype α-adducin in cell-free preparations (Ferrandi et al 1999).…”

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

“…Recombinant wild-type and mutant rat b-adducin were prepared according to previously published procedures (Ferrandi et al, 1999).…”

Antihypertensive therapy, the α-adducin polymorphism, and cardiovascular disease in high-risk hypertensive persons: the Genetics of Hypertension-Associated Treatment Study

“…7,12,[26][27][28][29][30][31][32] The overall evidence from these experimental and clinical studies indicates that Trp allele carriers have an increased risk of hypertension attributable to an innate stimulation of the sodium pump and enhanced renal tubular sodium reabsorption. 7,[33][34][35][36][37] However, most studies in humans suggest that mutation of the a-adducin gene on its own is insufficient to cause hypertension. 12 Indeed, the pathogenesis of high BP is complex, involves multiple genes, and lifestyle and environmental factors.…”