TRPV4 expression in the renal tubule is necessary for maintaining whole body K+ homeostasis.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-06-01 Epub Date: 2023-05-04 DOI:10.1152/ajprenal.00278.2022
Anna Stavniichuk, Kyrylo Pyrshev, Oleg Zaika, Viktor N Tomilin, Mariya Kordysh, Monika Lakk, David Križaj, Oleh Pochynyuk
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Abstract

The Ca2+-permeable transient receptor potential vanilloid type 4 (TRPV4) channel serves as the sensor of tubular flow, thus being well suited to govern mechanosensitive K+ transport in the distal renal tubule. Here, we directly tested whether the TRPV4 function is significant in affecting K+ balance. We used balance metabolic cage experiments and systemic measurements with different K+ feeding regimens [high (5% K+), regular (0.9% K+), and low (<0.01% K+)] in newly created transgenic mice with selective TRPV4 deletion in the renal tubule (TRPV4fl/fl-Pax8Cre) and their littermate controls (TRPV4fl/fl). Deletion was verified by the absence of TRPV4 protein expression and lack of TRPV4-dependent Ca2+ influx. There were no differences in plasma electrolytes, urinary volume, and K+ levels at baseline. In contrast, plasma K+ levels were significantly elevated in TRPV4fl/fl-Pax8Cre mice on high K+ intake. K+-loaded knockout mice exhibited lower urinary K+ levels than TRPV4fl/fl mice, which was accompanied by higher aldosterone levels by day 7. Moreover, TRPV4fl/fl-Pax8Cre mice had more efficient renal K+ conservation and higher plasma K+ levels in the state of dietary K+ deficiency. H+-K+-ATPase levels were significantly increased in TRPV4fl/fl-Pax8Cre mice on a regular diet and especially on a low-K+ diet, pointing to augmented K+ reabsorption in the collecting duct. Consistently, we found a significantly faster intracellular pH recovery after intracellular acidification, as an index of H+-K+-ATPase activity, in split-opened collecting ducts from TRPV4fl/fl-Pax8Cre mice. In summary, our results demonstrate an indispensable prokaliuretic role of TRPV4 in the renal tubule in controlling K+ balance and urinary K+ excretion during variations in dietary K+ intake. NEW & NOTEWORTHY The mechanoactivated transient receptor potential vanilloid type 4 (TRPV4) channel is expressed in distal tubule segments, where it controls flow-dependent K+ transport. Global TRPV4 deficiency causes impaired adaptation to variations in dietary K+ intake. Here, we demonstrate that renal tubule-specific TRPV4 deletion is sufficient to recapitulate the phenotype by causing antikaliuresis and higher plasma K+ levels in both states of K+ load and deficiency.

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TRPV4在肾小管中的表达对于维持全身K+稳态是必要的。
Ca2+可渗透的瞬时受体电位香草素4型(TRPV4)通道用作肾小管流量的传感器,因此非常适合控制远端肾小管中的机械敏感性K+转运。在这里,我们直接测试了TRPV4功能在影响K+平衡方面是否显著。我们在新创建的肾小管选择性TRPV4缺失的转基因小鼠(TRPV4fl/fl-Ax8Cre)及其同窝对照(TRPV4fl/fl)中使用了平衡代谢笼实验和不同K+喂养方案[高(5%K+)、常规(0.9%K+)和低(+)]的系统测量。通过TRPV4蛋白表达的缺失和TRPV4依赖性Ca2+内流的缺乏来验证缺失。在基线时,血浆电解质、尿量和K+水平没有差异。相反,TRPV4fl/fl-Ax8Cre小鼠在高K+摄入下血浆K+水平显著升高。K+负载敲除小鼠表现出比TRPV4fl/fl小鼠更低的尿K+水平,在第7天时伴有更高的醛固酮水平。此外,TRPV4fl/fl-Ax8Cre小鼠在饮食K+缺乏状态下具有更有效的肾脏K+保护和更高的血浆K+水平。TRPV4fl/fl-Ax8Cre小鼠在常规饮食中,尤其是在低K+饮食中,H+-K+-ATP酶水平显著升高,表明收集管中K+重吸收增强。一致地,我们发现,在TRPV4fl/fl-Ax8Cre小鼠的裂开的收集管中,细胞内酸化后,作为H+-K+-ATP酶活性的指标,细胞内pH恢复明显更快。总之,我们的研究结果表明,在饮食K+摄入变化期间,肾小管中TRPV4在控制K+平衡和尿K+排泄方面发挥着不可或缺的促钾作用。新的和值得注意的是,机械激活的瞬时受体电位香草素4型(TRPV4)通道在远端小管段表达,在那里它控制流量依赖性K+转运。全球TRPV4缺乏会导致对饮食K+摄入变化的适应受损。在这里,我们证明了肾小管特异性TRPV4缺失足以通过在K+负荷和缺乏状态下引起抗钾尿和较高的血浆K+水平来概括表型。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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