The Connexin40 A96S Mutation Causes Renin-Dependent Hypertension
The Connexin40 A96S Mutation Causes Renin-Dependent Hypertension
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DOI：
10.1681/asn.2010101047
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发表时间：
2011-06-01
影响因子：
13.6
通讯作者：
Kurtz, Armin
中科院分区：
文献类型：
--
作者：
Luebkemeier, Indra;Machura, Katharina;Kurtz, Armin
缝隙连接形成蛋白Cx40的缺失会导致小鼠的肾素依赖性高血压，但观察到的Cx40的人类变异，如A96S是否会促进高血压尚不清楚。在这里，我们产生了小鼠连接蛋白40基因中的A96S变体。虽然A96S突变纯合子小鼠肾脏中连接蛋白40的表达模式正常，但他们患有高血压，血浆肾素浓度比对照组高6倍，肾素mRNA水平比对照组高40%。A96S纯合子小鼠肾脏肾素表达细胞异常地位于传入小动脉中层外，肾脏灌流压升高并不抑制肾脏肾素分泌。低盐饮食与血管紧张素转换酶抑制剂联合治疗可增加肾素mRNA水平、血浆肾素浓度和异常定位的肾素产生细胞的数量。综上所述，这些发现表明，连接蛋白40的A96S突变导致了小鼠的肾素依赖性高血压。BP对肾素分泌的调节在很大程度上依赖于功能连接蛋白40；随着A96S突变，肾脏中肾素分泌细胞在血管外的异常定位可能会削弱压力介导的肾素分泌抑制。
Deletion of the gap-junction-forming protein connexin40 leads to renin-dependent hypertension in mice, but whether observed human variants in connexin40, such as A96S, promote hypertension is unknown. Here, we generated mice with the A96S variant in the mouse connexin40 gene. Although mice homozygous for the A96S mutations had normal expression patterns of connexin40 in the kidney, they were hypertensive, had sixfold higher plasma renin concentrations, and had 40% higher levels of renin mRNA than controls. Renin-expressing cells were aberrantly located outside the media layer of afferent arterioles, and increased renal perfusion pressure did not inhibit renin secretion from kidneys isolated from homozygous A96S mice. Treatment with a low-salt diet in combination with an ACE inhibitor increased renin mRNA levels, plasma renin concentrations, and the number of aberrantly localized renin-producing cells. Taken together, these findings suggest that the A96S mutation in connexin40 leads to renin-dependent hypertension in mice. Modulation of renin secretion by BP critically depends on functional connexin40; with the A96S mutation, the aberrant extravascular localization of renin-secreting cells in the kidney likely impairs the pressure-mediated inhibition of renin secretion.