BACKGROUND Regulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in β-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system. METHODS Using mice with mineralocorticoid receptor deletion in intercalated cells, we examined the mechanism and roles of pendrin upregulation via mineralocorticoid receptor in two different models of renin-angiotensin-aldosterone system activation. We also used aldosterone-treated NCC knockout mice to examine the role of pendrin regulation in salt-sensitive hypertension. RESULTS Deletion of mineralocorticoid receptor in intercalated cells suppressed the increase in renal pendrin expression induced by either exogenous angiotensin II infusion or endogenous angiotensin II upregulation via salt restriction. When fed a low-salt diet, intercalated cell-specific mineralocorticoid receptor knockout mice with suppression of pendrin upregulation showed BP reduction that was attenuated by compensatory activation of NCC. In contrast, upregulation of pendrin induced by aldosterone excess combined with a high-salt diet was scarcely affected by deletion of mineralocorticoid receptor in intercalated cells, but depended instead on hypokalemic alkalosis through the activated mineralocorticoid receptor-epithelial sodium channel cascade in principal cells. In aldosterone-treated NCC knockout mice showing upregulation of pendrin, potassium supplementation corrected alkalosis and inhibited the pendrin upregulation, thereby lowering BP. CONCLUSIONS In conjunction with NCC, the two pathways of pendrin upregulation, induced by angiotensin II through mineralocorticoid receptor activation in intercalated cells and by alkalosis through mineralocorticoid receptor activation in principal cells, play important roles in fluid homeostasis during salt depletion and salt-sensitive hypertension mediated by aldosterone excess.

中文翻译：

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远端肾单位中Pendrin活化的两种盐皮质激素受体介导的机制。

背景技术对醛固酮敏感的远端肾单位中氯化钠运输的调节对于流体稳态和血压控制是必不可少的。β插入细胞中的氯化物-碳酸氢盐交换物Pendrin以及远端回旋小管中的氯化钠共转运蛋白（NCC）共同调节氯化钠的处理，这由肾素-血管紧张素-醛固酮系统控制。方法使用在插入细胞中具有盐皮质激素受体缺失的小鼠，我们研究了在两种不同模型的肾素-血管紧张素-醛固酮系统激活中，通过盐皮质激素受体引起的戊达德上调的机制和作用。我们还使用了醛固酮治疗的NCC基因敲除小鼠来检查Pendrin调节在盐敏感性高血压中的作用。结果插入细胞中盐皮质激素受体的缺失抑制了外源性血管紧张素II输注或内源性血管紧张素II通过盐限制上调引起的肾Pendrin表达的增加。当喂食低盐饮食时，插入的细胞特异性盐皮质激素受体敲除小鼠抑制了Pendrin的上调，显示BP降低，其被NCC的代偿性激活减弱。相比之下，醛固酮过量与高盐饮食联合引起的Pendrin上调几乎不受插层细胞中盐皮质激素受体缺失的影响，而是依赖于主要细胞中活化的盐皮质激素受体-上皮钠通道级联的低钾性碱中毒。在醛固酮治疗的NCC基因敲除小鼠中显示出Pendrin的上调，补充钾可纠正碱中毒并抑制Pendrin上调，从而降低BP。结论与NCC结合，血管紧张素II通过插层细胞中的盐皮质激素受体激活和主要细胞中盐皮质激素受体的活化引起碱中毒引起的Pendrin上调的两种途径在盐耗竭和盐敏感性高血压介导的液体稳态中起重要作用醛固酮过量。