Transgenic Mice Overexpressing Human Alpha-1 Antitrypsin Exhibit Low Blood Pressure and Altered Epithelial Transport Mechanisms in the Inactive and Active Cycles.
Transgenic Mice Overexpressing Human Alpha-1 Antitrypsin Exhibit Low Blood Pressure and Altered Epithelial Transport Mechanisms in the Inactive and Active Cycles.
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DOI：
10.3389/fphys.2021.710313
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发表时间：
2021
影响因子：
4
通讯作者：
Alli AA
中科院分区：
文献类型：
--
作者：
Liu LP;Gholam MF;Elshikha AS;Kawakibi T;Elmoujahid N;Moussa HH;Song S;Alli AA
人α-1抗胰蛋白酶（hAAT）是一种多功能的蛋白酶抑制剂，但其作用靶点在醛固酮敏感的远端肾单位及其在电解质平衡和血压控制中的作用尚不清楚。我们分析了尿电解质，渗透压和血压从hAAT转基因（hAAT-Tg）小鼠和C57 B/6野生型对照小鼠维持在正常盐或高盐饮食。尿钠，钾，氯离子浓度以及尿渗透压较低的hAAT-Tg小鼠维持高盐饮食期间的活动和非活动周期。当维持正常盐饮食时，hAAT-Tg小鼠与C57 B6小鼠相比显示出较低的收缩压，但当维持高盐饮食时没有观察到这一点。与野生型对照相比，hAAT-Tg小鼠中的组织蛋白酶B蛋白活性较低。在hAAT-Tg小鼠中，钠上皮通道（ENaC）α的α亚基的蛋白表达也降低。与野生型对照组相比，hAAT-Tg小鼠肾皮质膜组分中的利钠肽受体C（NPRC）蛋白表达减少，而心钠肽（ANP）的循环水平更高。本研究表征了hAAT-Tg小鼠在非活动和活动周期期间的电解质和血压表型，并研究了ENaC活化部分被抑制的机制，该机制涉及体循环中组织蛋白酶B活性降低和ANP水平升高。
Human alpha-1 antitrypsin (hAAT) is a versatile protease inhibitor, but little is known about its targets in the aldosterone-sensitive distal nephron and its role in electrolyte balance and blood pressure control. We analyzed urinary electrolytes, osmolality, and blood pressure from hAAT transgenic (hAAT-Tg) mice and C57B/6 wild-type control mice maintained on either a normal salt or high salt diet. Urinary sodium, potassium, and chloride concentrations as well as urinary osmolality were lower in hAAT-Tg mice maintained on a high salt diet during both the active and inactive cycles. hAAT-Tg mice showed a lower systolic blood pressure compared to C57B6 mice when maintained on a normal salt diet but this was not observed when they were maintained on a high salt diet. Cathepsin B protein activity was less in hAAT-Tg mice compared to wild-type controls. Protein expression of the alpha subunit of the sodium epithelial channel (ENaC) alpha was also reduced in the hAAT-Tg mice. Natriuretic peptide receptor C (NPRC) protein expression in membrane fractions of the kidney cortex was reduced while circulating levels of atrial natriuretic peptide (ANP) were greater in hAAT-Tg mice compared to wild-type controls. This study characterizes the electrolyte and blood pressure phenotype of hAAT-Tg mice during the inactive and active cycles and investigates the mechanism by which ENaC activation is inhibited in part by a mechanism involving decreased cathepsin B activity and increased ANP levels in the systemic circulation.
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影响因子：
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