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Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension
Juliette Hadchouel, Christelle Soukaseum, Cara Büsst, Xiao-ou Zhou, Véronique Baudrie, Tany Zürrer, Michelle Cambillau, Jean-Luc Elghozi, Richard P. Lifton, Johannes Loffing, Xavier Jeunemaitre and Maurice B. Burg
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 42 (October 19, 2010), pp. 18109-18114
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25748447
Page Count: 6
You can always find the topics here!Topics: Hypertension, Urine, Protein isoforms, Phosphorylation, Kidneys, Physiological regulation, Mice, Diet, Gene expression regulation, Diastolic blood pressure
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Mutations in WNK1 and WNK4 lead to familial hyperkalemic hypertension (FHHt). Because FHHt associates net positive Na⁺ balance together with K⁺ and H⁺ renal retention, the identification of WNK1 and WNK4 led to a new paradigm to explain how aldosterone 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-Cl 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 suggested that the activation of NCC plays a central role in the development 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–Cl cotransporter is not sufficient by itself to induce a hyperkalemic hypertension and that the deregulation of other channels, such as the Epithelial Na⁺ channel (ENaC), is probably required.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences