The Milan hypertensive strain of rats (MHS) develops a genetic form of renal hypertension that, when compared to its normotensive control (MNS), shows renal dysfunction similar to that of a subset of human patients with primary hypertension. MHS and MNS were shown to be homozygous by multilocus miisatellite analysis and monolocus microsatellite markers. We show here that one point mutation in each of two genes coding for the membrane skeleton protein adducin is associated with blood pressure in the Milan strain of rats. Adducin is a heterodimer formed by a and 13 subunits that promotes the assembly of actin with spectrin. MHS and MNS differ, respectively, by the amino acids Y and F at position 316 of the a subunit. In the ,&adducin locus, MRS is always homozygous for R at position 529 while in MNS either R or Q occurs in that position. The R/Q heterozygotes showed lower blood pressure than any of the homozygotes. In vitro phosphorylation studies suggest that both of these amino acid substitutions occur within protein kinase recognition sites. Analysis of an F2 generation demonstrated that Y alleles segregated with a significant increment in blood pressure. This effect is modulated by the presence of the R allele of the 1 subunit. Taken together, these dings strongly support a role for adducin polymorphisms in causing variation of blood pressure in the Milan strain of rats.
The significance of the erythrocyte abnormalities described in rats and humans with spontaneous hypertension is far from clear. This study, in two highly inbred strains of rats, was designed to evaluate whether these abnormalities are primary and thus genetically related to hyper-tension. The Milan hypertensive strain (MHS) and its normotensive control strain (MNS) were used to carry out two types of experiments. In two groups of lethally irradiated (MHS x MNS) F, hybrids, bone marrow from MHS or MNS was transplanted. The differences in red cell function between the recipients of bone marrow from MHS and recipients of bone marrow from MNS were similar to those existing between the parental donor MHS and MNS: Na +-K + cotransport was increased (p < 0.02) and intracellular Na + content (p < 0.05) and cell volume (p < 0.02) were decreased in MHS. The same pattern was observed when this experiment was repeated in different groups of F, hybrids. In individuals of the segregating F 2 population, obtained by crossing the (MHS x MNS) F, hybrids, there was a positive correlation (p < 0.001) between the red blood cell Na +-K + cotransport and the mean blood pressure. These results indicate that the erythrocyte abnormalities may well be genetically associated with the primary cause of spontaneous hypertension in rats. Because of the many similarities demonstrated when young prehypertensive MHS or humans prone to develop hypertension are compared with their respective controls, it is possible that the findings described here in rats are relevant to human essential hypertension. (Hypertension 7: 319-325, 1985) KEY WORDS • red blood cell • genetic hypertension • cell volume • ion transport T HE cause of essential hypertension is not known. It is generally accepted that hyperten-sion develops when there is increased genetic sensitivity to certain environmental stimuli 1 and that red blood cell (RBC) membrane functions are abnormal in humans with essential hypertension 2 " 6 and rats with spontaneous hypertension. 7 '" It is not clear whether these alterations in red cell cation transport are the result of chance genetic selection unrelated to the cause of hypertension, are secondary to the hyperten-sive disease, or are the direct phenotypic expression of the same genetic abnormalities responsible for the increased susceptibility to hypertension. We must determine which of these possibilities is responsible if we wish to use the RBC transport systems as probes to study the genetic mechanisms of arterial hypertension. We have approached these questions by using two highly inbred strains of rats, the Milan hypertensive strain (MHS, inbreeding coefficient 0.988) and its nor-motensive control (MNS, inbreeding coefficient 0.989). Previous studies 12 " 14 with MHS and MNS showed many pathophysiological similarities between their hypertension and essential hypertension in humans. Kidney cross-transplantation and renal function studies suggested that the hypertension of MHS might originate from a primary increase in the transport of Na...
1. The aim of this study was to compare certain renal and erythrocyte functions in the Milan hypertensive strain (MHS) of rats and in normotensive control animals (MNS).2. Under experimental conditions close to those in conscious unmanipulated animals, the glomerular filtration rate (GFR) per g kidney weight was higher and the kidney weight/body weight ratio lower in MHS than in MNS rats (P < 0-001). This suggests that there is increased transtubular ion transport in MHS animals.3. The MHS rats had a higher rate constant for outward Na+-K+ cotransport than the MNS animals (P < 0.02), their intra-erythrocyte sodium concentrations were lower (P < 0.05) and their erythrocyte volume was smaller ( P < 0.00 1). Therefore, accelerated cell membrane sodium outward cotransport seems to reset the volume and the sodium content of the erythrocytes of MHS rats at a lower level.4. We speculate that increased transport of ions across the cell membrane may be an abnormality common to erythrocytes and renal tubular cells in MHS rats.
Previous studies on the pathogenetic mechanisms of hypertension in the Milan hypertensive strain of rat (MHS)showed that a polymorphism within the a-adducin gene is responsible for up to 50% of the blood pressure difference between MHS and their MNS normotensive control strain. A case-control study has shown also in humans an association between a-adducin locus and hypertension using 4 multiallelic markers surrounding the a-adducin locus.2. With a multiple regression approach we provide an estimate of the contribution of the genotype for each marker to the blood pressure variability in comparison to that provided by sex, body mass index and age.3. While sex, body mass index and age contributed by about 40-45% to the overall blood pressure variability, the inclusion of the genotype for the marker closer to the a-adducin locus provided a further increase of the variability explained of about 5%. 4. The contribution independently provided by the other markers decreased exponentially with the increase of distance from a-adducin locus.There is common agreement that the different animal models of genetic hypertension mirror a fraction of the clinical heterogeneity of human essential hypertension. The Milan hypertensive strain of rats (MHS) shares many pathophysiological analogies with a subgroup of hypertensive subjects (Bianchi et al. 1990). However, up to few years ago only circumstantial evidence supported these analogies, based mainly on the observation of increased glomerular filtration rate and renal plasma flow before the development of hypertension, depressed plasma renin activity and faster membrane ion transport (Bianchi et al. 1990;Cusi et al. 1993). A point mutation causing amino-acid substitution in each of the two genes coding for the a and fl subunit of adducin is present in M H S rats (Bianchi et al. 1944). The mutation of a-adducin accounted for the most significant blood pressure variation while that on the subunit was only modulating the effect of a subunit (Bianchi et al. 1994). In humans also hypertension may be influenced by functional mutations within the a-adducin gene. This was suggested by the findings from a case-control study where we found that some allelic forms of a multiallelic mini-satellite marker (D4S95) mapping very close to the adducin locus (20 kb) were strongly and significantly associated with hypertension. The association weakened and disappeared for markers mapping farther from a-adducin locus (Casari et al. 1995). We present a preliminary analysis of the effect of different possible genotypes for the already studied markers on the blood pressure variability on the same set of patients and controls. METHODS Patients and controlsOne hundred and ninety essential hypertensive patients and 126 normotensive controls were recruited for the study. They were all unrelated, Caucasian, living within the metropolitan area of Milan and were free of disease. Selected hypertensives had to be less than 60 years of age at the time of onset of hypertension, and a blood pressure higher than 15...
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