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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney- specific isoform of WNK1 and prevents hypertension
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Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney- specific isoform of WNK1 and prevents hypertension

机译：ENaC表达的降低补偿了WNK1肾脏特异性亚型失活后NCC活性的增加，并预防了高血压

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摘要

Mutations in WNK1 and WNK4 lead to familial hyperkalemic hy-pertension (FHHt). Because FHHt associates net positive Na~+ bal-ance together with K~+ and H~+ renal retention, the identification of WNK1 and WNK4 led to a new paradigm to explain how aldoste-rone can promote either Na~+ reabsorption or K~+ secretion in a hypovolemic or hyperkalemic state, respectively. WNK1 gives rise to L-WNK1, an ubiquitous kinase, and KS-WNK1, a kinase-defective isoform expressed in the distal convoluted tubule. By inactivating KS-WNK1 in mice, we show here that this isoform is an important regulator of sodium transport. KS-WNK1~(-/-) mice display an increased activity of the Na-CI cotransporter NCC, expressed specifically in the distal convoluted tubule, where it participates in the fine tuning of sodium reabsorption. Moreover, the expression of the ROMK and BKCa potassium channels was modified in KS-WNK1~(-/-) mice, indicating that KS-WNK1 is also a regulator of potassium transport in the distal nephron. Finally, we provide an alternative model for FHHt. Previous studies sug-gested that the activation of NCC plays a central role in the de-velopment of hypertension and hyperkalemia. Even though the increase in NCC activity in KS-WNK1~(-/-) mice was less pronounced than in mice overexpressing a mutant form of WNK4, our study suggests that the activation of Na-CI cotransporter is not sufficient by itself to induce a hyperkalemic hypertension and that the de-regulation of other channels, such as the Epithelial Na+ channel (ENaC), is probably required.
机译：WNK1和WNK4中的突变导致家族性高钾血症性高血压（FHHt）。由于FHHt将净的Na〜+阳性平衡与K〜+和H〜+的肾脏retention留联系在一起，因此WNK1和WNK4的鉴定导致了一个新的范式，说明醛固酮可以促进Na〜+重吸收或K〜 +分别以低血容量或高血钾状态分泌。 WNK1产生L-WNK1，一种普遍存在的激酶，而KS-WNK1，一种在远端回旋小管中表达的激酶缺陷型亚型。通过灭活小鼠中的KS-WNK1，我们在这里表明该同工型是钠转运的重要调节剂。 KS-WNK1〜（-/-）小鼠表现出Na-CI协同转运蛋白NCC的活性增强，特别是在远曲小管中表达，它参与了钠重吸收的微调。此外，在KS-WNK1〜（-/-）小鼠中，ROMK和BKCa钾通道的表达被修饰，表明KS-WNK1也是远端肾单位中钾转运的调节剂。最后，我们提供了FHHt的替代模型。先前的研究表明，NCC的激活在高血压和高钾血症的发展中起着核心作用。尽管KS-WNK1〜（-/-）小鼠中NCC活性的增加不如过表达WNK4突变型的小鼠明显，但我们的研究表明Na-CI共转运蛋白本身的激活不足以诱导ACC转运。高钾血症性高血压以及其他通道（例如上皮Na +通道（ENaC））的调节可能是必需的。

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    Juliette Hadchouel; Christelle Soukaseum; Cara Buesst; Xiao-ou Zhou; Veronique Baudrie; Tany Zuerrer; Michelle Cambillau; Jean-Luc Elghozi; Richard P. Lifton; Johannes Loffing; Xavier Jeunemaitre;

  • 作者单位

    Institut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France;

    rnInstitut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France;

    rnInstitut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France;

    rnInstitut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France;

    rnInstitut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France;

    rnInstitute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland;

    rnDepartment of Biochemistry, Assistance Publique-Hopitaux de Paris, Hdpital Europeen Georges Pompidou, F-75015 Paris, France;

    rnInstitut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France;

    rnDepartment of Genetics, Howard Hughes Medical Institute Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, CT 06510;

    rnInstitute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland;

    rnInstitut National de la Sante et de la Recherche Medicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France University Paris-Descartes, F-75015 Paris, France Department of Genetics, Assistance Publique-Hopitaux de Paris,Hdpital Europeen Georges Pompidou, F-75015 Paris, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    transgenic animals; water-electrolyte balance;

    机译：转基因动物水电解质平衡;

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