Pendrin-null mice develop severe hypokalemia following dietary Na+ and K+ restriction: role of ENaC.
Pendrin-null mice develop severe hypokalemia following dietary Na+ and K+ restriction: role of ENaC.
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Pendrin-null 小鼠在饮食钠和钾限制后出现严重的低钾血症：ENaC 的作用。
DOI：
10.1152/ajprenal.00378.2021
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Wall,SusanM
中科院分区：
文献类型：
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作者：
Pham,TruyenD;Elengickal,AnthonyJ;Verlander,JillW;Al-Qusairi,Lama;Chen,Chao;Abood,DelaneyC;King,SpencerA;Loffing,Johannes;Welling,PaulA;Wall,SusanM
Pendrin是一种插层细胞Cl−/交换剂，被认为参与了K+-节约NaCl的吸收。然而，其在K+稳态中的作用尚未明确。我们假设pendrin缺失的小鼠在饮食中限制K+后会出现低钾血症。我们进一步假设penddrin敲除（KO）小鼠通过下调上皮Na+通道（ENaC）来减轻尿K+损失。因此，我们研究了ENaC在pendrin KO和野生型小鼠饮食K+限制后Na+和K+平衡中的作用。为此，我们检测了K+限制性pdrin -null和NaCl限制或充满的野生型小鼠Na+和K+平衡与ENaC亚基丰度之间的关系。在全盐、限钾饮食后，两组的K+平衡和血清K+相似。然而，在缺乏Na+、K+和Cl−的饮食后，pendrin KO小鼠因K+排泄增加而出现低钾血症。在ENaC刺激下，K+受限的pendrin KO小鼠血清K+的下降增强，而ENaC抑制则消除。在ENaC刺激下，K+受限的pendrin KO小鼠血清K+的下降增强，而ENaC抑制则消除。然而，ENaC活性的降低也降低了血压，增加了血管内体积的明显收缩，因为KO小鼠有较低的血清Na+，较高的血尿素氮和血红蛋白，更大的体重减轻，更大的代谢性碱中毒和更多的NaCl排泄。我们得出结论，饮食中Na+和K+限制可引起pendrin KO小鼠低钾血症。Pendrin-null小鼠通过下调ENaC抑制肾K+损失。然而，这种ENaC下调是以牺牲血管内容量为代价的。ypendrin是一种根尖Cl−/交换剂，可提供肾脏保留K+的NaCl吸收。无pendin的肾脏不能完全保存K+，并通过下调上皮Na+通道（ENaC）来限制肾K+的损失。然而，在Na+限制下，为了K+平衡而降低ENaC的需求与为了血管内容积而刺激ENaC的需求相冲突。因此，与野生型小鼠相比，NaCl限制对pendrin缺失小鼠ENaC的刺激更少，从而减轻了它们的钾尿症和低钾血症，但加剧了体积收缩。
Pendrin is an intercalated cell Cl−/exchanger thought to participate in K+-sparing NaCl absorption. However, its role in K+homeostasis has not been clearly defined. We hypothesized that pendrin-null mice will develop hypokalemia with dietary K+restriction. We further hypothesized that pendrin knockout (KO) mice mitigate urinary K+loss by downregulating the epithelial Na+channel (ENaC). Thus, we examined the role of ENaC in Na+and K+balance in pendrin KO and wild-type mice following dietary K+restriction. To do so, we examined the relationship between Na+and K+balance and ENaC subunit abundance in K+-restricted pendrin-null and wild-type mice that were NaCl restricted or replete. Following a NaCl-replete, K+-restricted diet, K+balance and serum K+were similar in both groups. However, following a Na+, K+, and Cl−-deficient diet, pendrin KO mice developed hypokalemia from increased K+excretion. The fall in serum K+observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. The fall in serum K+observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. However, reducing ENaC activity also reduced blood pressure and increased apparent intravascular volume contraction, since KO mice had lower serum Na+, higher blood urea nitrogen and hemoglobin, greater weight loss, greater metabolic alkalosis, and greater NaCl excretion. We conclude that dietary Na+and K+restriction induces hypokalemia in pendrin KO mice. Pendrin-null mice limit renal K+loss by downregulating ENaC. However, this ENaC downregulation occurs at the expense of intravascular volume.NEW & NOTEWORTHYPendrin is an apical Cl−/exchanger that provides renal K+-sparing NaCl absorption. The pendrin-null kidney has an inability to fully conserve K+and limits renal K+loss by downregulating the epithelial Na+channel (ENaC). However, with Na+restriction, the need to reduce ENaC for K+balance conflicts with the need to stimulate ENaC for intravascular volume. Therefore, NaCl restriction stimulates ENaC less in pendrin-null mice than in wild-type mice, which mitigates their kaliuresis and hypokalemia but exacerbates volume contraction.