Disturbed homeostasis in sodium-restricted mice heterozygous and homozygous for aldosterone synthase gene disruption
Disturbed homeostasis in sodium-restricted mice heterozygous and homozygous for aldosterone synthase gene disruption
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DOI：
10.1161/01.hyp.0000249902.09036.e7
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发表时间：
2006-12-01
期刊：
影响因子：
8.3
通讯作者：
Smithies, Oliver
中科院分区：
文献类型：
--
作者：
Makhanova, Natalia;Sequeira-Lopez, Maria L. S.;Smithies, Oliver
我们已经确定，醛固酮合成酶（AS）的表达差异影响对低盐饮食的反应。在AS基因敲除小鼠（AS-/-）中，低盐显著降低血浆钠和增加钾，但在野生型小鼠中没有。正常盐AS（-/-）小鼠中存在的尿量增加（1.5 X野生型）和尿渗透压降低（0.7 X野生型）在低盐时变得更加严重（2.3 X野生型和0.5 X野生型），但野生型中均未发生变化。在这两种基因型中，血浆加压素在正常和低盐下相似，去氨加压素注射液显著增加尿渗透压。肾脏水通道蛋白1和3的mRNA水平不受基因型或饮食的影响，上皮钠通道和Na+-K+-2Cl（-）-协同转运蛋白的基因型影响。在AS（-/-）小鼠中，水通道蛋白2 mRNA在正常盐下增加，而Na+Cl-协同转运蛋白和皮质K+通道mRNA在两种饮食下均减少。AS（-/-）小鼠的低血压进一步降低低盐，尽管额外增加的肾素，肾内动脉壁厚度，和致密斑环化酶-2 mRNA。在正常盐的AS（-/-）小鼠中，肾上腺AS mRNA略有下降（0.7 X野生型），但血压正常。在低盐条件下，他们的血压低于野生型（101 +/- 2 mm Hg vs 106 +/- 2 mm Hg），即使肾素mRNA增加到野生型的2倍。我们的结论是，醛固酮是至关重要的尿液浓度和维持血压，甚至轻微减少AS表达使血压敏感低盐，这表明在人类AS水平的遗传差异可能会影响血压如何响应饮食中的盐。
We have determined that differences in expression of aldosterone synthase ( AS) affect responses to a low-salt diet. In AS-null mice (AS-/-), but not in wild-type, low salt significantly decreased plasma sodium and increased potassium. The increased urine volume (1.5 X wild-type) and decreased urine osmolality (0.7 X wild-type), present in AS(-/-) mice on normal salt, became more severe (2.3 X wild-type and 0.5 X wild-type) on low salt, but neither changed in wild-type. In both genotypes, plasma vasopressin was similar on normal and low salt, and desmopressin injection significantly increased urine osmolality. Renal mRNA levels for aquaporin 1 and 3 were unchanged by genotype or diet and epithelial sodium channel and Na+-K+-2Cl(-)-cotransporter by genotype. In AS(-/-) mice, aquaporin 2 mRNA increased on normal salt, whereas Na+Cl--cotransporter and cortex K+ channel mRNAs decreased on both diets. The low blood pressure of AS(-/-) mice was decreased further by low salt, despite additional increases in renin, intrarenal arterial wall thickness, and macula densa cyclogenase-2 mRNA. In AS(-/-) mice on normal salt, adrenal AS mRNA was slightly decreased (0.7 X wild-type), but blood pressure was normal. On low salt, their blood pressure was less than wild-type (101 +/- 2 mm Hg versus 106 +/- 2 mm Hg), even though renin mRNA increased to 2 X wild-type. We conclude that aldosterone is critical for urine concentration and maintenance of blood pressure and even a mild reduction of AS expression makes blood pressure sensitive to low salt, suggesting that genetic differences of AS levels in humans may influence how blood pressure responds to dietary salt.