Abstract :
Comparisons of Milan hypertensive strain of rats (MHS) with its control normotensive strain (MNS) for measurements of renal function in whole animal and isolated organ, blood pressure after kidney cross transplantations, ion transport across plasma membrane in tubular cells and erythrocytes of parental strains and genetic crosses, were all consistent with the hypothesis that a faster ion transport across the plasma membrane could be responsible for, at least, a portion of the blood pressure (BP) difference between the two strains. The ion transport difference in erythrocytes disappeares after removal of the membrane skeleton and cross-immunization studies showed an immunochemical difference in a membrane skeleton protein subsequently identified as adducin. The genes coding for α and β adducin in MHS and MNS were sequenced and an one point mutation in each subunit causing an aminoacid substitution was detected (Y and F in α subunit and R and Q in β respectively for MHS and MNS genes). Analysis of an F2 generation demonstrated that α-Y MHS allele segregated with a significant increment in blood pressure and lower kidney weight and that this BP effect was modulated by presence of the R allele in the β subunit.
Isolation of congenic substrains differing only by these alleles is in progress to test possible association between the adducin polymorphism, the ion transport and the renal functional abnormalities responsible for the blood pressure differences between MHS and MNS rats.
To evaluate possible association between the α adducin locus and hypertension in man, a case control study was carried out in 190 hypertensives and 126 controls by measuring four multi-allelic markers surrounding the α-adducin locus located in 4 p 16.3. The maximum association (X2=13.3) occurred for the D4S95 marker which maps closest (20 Kb) to adducin, while association of the other markers with blood pressure decreases as their distance from the adducin locus increases.
Therefore the membrane skeleton protein adducin may be involved in blood pressure regulation both in rat and in man.
