Collecting duct-specific knockout of endothelia-1 causes hypertension and sodium retention
Collecting duct-specific knockout of endothelia-1 causes hypertension and sodium retention
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DOI：
10.1172/jci200421064
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发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Kohan, DE
中科院分区：
文献类型：
--
作者：
Ahn, D;Ge, YQ;Kohan, DE
体外研究表明，集合管衍生的（CD衍生的）内皮素-1（ET-1）可以调节肾脏钠重吸收;然而，CD衍生的ET-1的生理作用尚不清楚。因此，确定了在小鼠CD中选择性破坏ET-1基因的生理效应。生成水通道蛋白2启动子Cre重组酶杂合和ET-1基因loxP侧翼外显子2纯合的小鼠（称为ET-1的CD特异性KO [CD ET-1 KO]小鼠）。这些动物没有CD ET-1 mRNA，尿ET-1排泄减少。正常钠饮食的CD ET-1 KO小鼠高血压，而体重，钠排泄，尿醛固酮排泄和血浆肾素活性不变。高钠饮食的CD ET-1 KO小鼠高血压恶化，尿钠排泄减少，体重增加过多，但醛固酮排泄和血浆肾素活性之间没有差异。阿米洛利或呋塞米降低正常或高钠饮食的CD ET-1 KO小鼠的血压，并防止盐负荷CD ET-1 KO小鼠的过度钠潴留。这些研究表明，CD衍生的ET-1是肾钠排泄和全身血压的重要生理调节剂。
In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown. Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined. Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated. These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion. CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity. Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice. These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP.