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A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of tenal tubular acidosis

Abstract : Pseudohypoaldosteronism type II (PHAII) is a rare monogenic disease characterized by the association of hyperkalemia, hyperchloremic metabolic acidosis and hypertension. It is produced by mutations in the WNK1, WNK4, KLHL3 or CUL3 genes. The clinical manifestations of PHAII are due to an increased activity of the thiazide-sensitive Na+-Cl- cotransporter NCC, expressed in the distal convoluted tubule. However, the increased NCC activity do not fully explain the physiopathology of PHAII, giving evidence that other renal transport systems are altered in this disease. It has been reported that WNK4 is expressed not only in the DCT cells but also in -intercalated cells of the cortical collecting duct. These cells exchange intracellular HCO3- for external Cl- through pendrin, and therefore, account for renal base excretion. They can also mediate electroneutral thiazide-sensitive NaCl absorption when pendrin-dependent apical Cl- influx is coupled to apical Na+ influx by the Na+-driven Cl-/HCO3- exchanger NDCBE. Taking advantage of a mouse model (TgWNK4PHAII) carrying a WNK4 missense mutation (Q562E) identified in PHAII patients, the purpose of this study was to determine whether the electroneutral Na+-Cl- absorption through pendrin/NDCBE is involved in the pathogenesis of this disease. Our results show that renal pendrin activity is markedly increased in TgWNK4PHAII mice, leading to an increase in thiazide-sensitive NaCl absorption by the collecting duct and contributing to metabolic acidosis. Thus, pendrin genetic ablation in TgWNK4PHAII mice corrects the metabolic acidosis and also the hyperkalemia characteristic of PHAII.
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Submitted on : Monday, August 31, 2020 - 2:25:27 PM
Last modification on : Wednesday, October 14, 2020 - 4:08:59 AM


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  • HAL Id : tel-02926159, version 1


Irma Karen López-Cayuqueo. A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of tenal tubular acidosis. Tissues and Organs [q-bio.TO]. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS465⟩. ⟨tel-02926159⟩



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