A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis
A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis
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DOI：
10.1016/j.kint.2018.05.001
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发表时间：
2018-09-01
影响因子：
19.6
通讯作者：
Chambrey，Regine
中科院分区：
文献类型：
--
作者：
Lopez-Cayuqueo，Karen I.;Chavez-Canales，Maria;Chambrey，Regine
假性醛固酮减少症II型（PHAII）是一种遗传性疾病，以高钾血症、高氯血症代谢性酸中毒、高血压、低肾素和对噻嗪类利尿剂高度敏感为特征。它是由wnk1、WNK4、klhl3或cul3基因突变引起的。有强有力的证据表明，远曲小管中氯化钠共转运体NCC的过量氯化钠重吸收与此有关。WNK4不仅在远曲小管细胞中表达，也在皮质集管的β -嵌入细胞中表达。后一种细胞通过penddrin将细胞内的碳酸氢盐交换为外部的氯化物，因此可以解释肾碱排泄。然而，当钠驱动的氯化物/碳酸氢盐交换剂将依赖于penddrin的根尖氯离子内流与根尖钠离子内流耦合时，这些细胞也可以介导噻嗪类药物敏感的氯化钠吸收。在这里，我们确定该系统是否参与了PHAII的发病机制。在先前在PHAII患者中发现的携带WNK4错义突变（Q562E）的小鼠模型中，肾penddrin活性显着增加。penddrin的上调导致皮质集管对噻嗪类药物敏感的氯化钠吸收增加，引起代谢性酸中毒。在这个模型中，根尖钾通道的功能发生了改变，高钾血症通过pendrin基因消融得到了完全纠正。因此，我们证明了penddrin在肾脏对氯化钠、钾和酸碱稳态的调节以及PHAII的病理生理方面的重要贡献。此外，我们确定肾脏远端碳酸氢盐分泌是肾小管酸中毒的新机制。
Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in theWNK1,WNK4,KLHL3orCUL3gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in β−intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.