TRPV4 deletion protects against hypokalemia during systemic K+ deficiency.
TRPV4 deletion protects against hypokalemia during systemic K+ deficiency.
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TRPV4 缺失可防止全身缺钾期间出现低钾血症。
DOI：
10.1152/ajprenal.00043.2019
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Pochynyuk,Oleh
中科院分区：
文献类型：
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作者：
Tomilin,Viktor;Mamenko,Mykola;Zaika,Oleg;Wingo,CharlesS;Pochynyuk,Oleh
K+平衡的严格调节是正常生理的基础。在西方饮食中常见的饮食K+摄入量减少，通常会导致低钾血症和相关的心血管和肾脏相关疾病。远端肾单位，特别是集合管（CD），是通过H+-K+-ATP酶在膳食K+缺乏状态下控制K+重吸收的主要部位。我们（Mamenko MV，Boukelmoune N，Tomilin VN，Zaika OL，詹森VB，O 'Neil RG，Pochynyuk OM.Kidney Int 91：1398-1409，2017）之前已经证明，CD中大量表达的瞬时受体电位香草酸4型（TRPV 4）Ca 2+通道通过促进流动诱导的K+分泌来促进肾脏K+处理。在这里，我们研究了TRPV 4在控制CD中H+-K+-ATP酶依赖的K+重吸收中的潜在作用。用缺乏K+的饮食（<0.01%K+）处理7天，使野生型（WT）小鼠的血清K+水平从4.3 ± 0.2 mM降至3.3 ± 0.2 mM，但TRPV 4 −/−小鼠的血清K+水平没有降低（分别为4.3 ± 0.1和4.2 ± 0.3 mM）。此外，我们检测到TRPV 4 −/−小鼠在转换为K+缺乏饮食后，24小时尿K+水平与WT小鼠相比显著降低。TRPV 4 −/−动物在低K+饮食中也有明显更多的酸性尿液，但在常规（0.9%K+）或高K+（5%K+）饮食中则没有，这与H+-K+-ATP酶活性增加一致。此外，我们检测到与喂食K+缺乏饮食的WT小鼠相比，TRPV 4 −/−新鲜分离的CD中H+-K+-ATP酶依赖性细胞内pH挤出大大加速。总之，我们的研究结果表明TRPV 4通过抑制CD中H+-K+-ATP酶依赖的K+重吸收而发挥新的排钾作用。我们认为，TRPV 4抑制可能是一种新的策略，在临床环境中管理某些低钾状态。
Tight regulation of K+balance is fundamental for normal physiology. Reduced dietary K+intake, which is common in Western diets, often leads to hypokalemia and associated cardiovascular- and kidney-related pathologies. The distal nephron, and, specifically, the collecting duct (CD), is the major site of controlled K+reabsorption via H+-K+-ATPase in the state of dietary K+deficiency. We (Mamenko MV, Boukelmoune N, Tomilin VN, Zaika OL, Jensen VB, O'Neil RG, Pochynyuk OM.Kidney Int91: 1398–1409, 2017) have previously demonstrated that the transient receptor potential vanilloid type 4 (TRPV4) Ca2+channel, abundantly expressed in the CD, contributes to renal K+handling by promoting flow-induced K+secretion. Here, we investigated a potential role of TRPV4 in controlling H+-K+-ATPase-dependent K+reabsorption in the CD. Treatment with a K+-deficient diet (<0.01% K+) for 7 days reduced serum K+levels in wild-type (WT) mice from 4.3 ± 0.2 to 3.3 ± 0.2 mM but not in TRPV4−/−mice (4.3 ± 0.1 and 4.2 ± 0.3 mM, respectively). Furthermore, we detected a significant reduction in 24-h urinary K+levels in TRPV4−/−compared with WT mice upon switching to K+-deficient diet. TRPV4−/−animals also had significantly more acidic urine on a low-K+diet, but not on a regular (0.9% K+) or high-K+(5% K+) diet, which is consistent with increased H+-K+-ATPase activity. Moreover, we detected a greatly accelerated H+-K+-ATPase-dependent intracellular pH extrusion in freshly isolated CDs from TRPV4−/−compared with WT mice fed a K+-deficient diet. Overall, our results demonstrate a novel kaliuretic role of TRPV4 by inhibiting H+-K+-ATPase-dependent K+reabsorption in the CD. We propose that TRPV4 inhibition could be a novel strategy to manage certain hypokalemic states in clinical settings.