Furosemide reduces BK-αβ4-mediated K+ secretion in mice on an alkaline high-K+ diet.
Furosemide reduces BK-αβ4-mediated K+ secretion in mice on an alkaline high-K+ diet.
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呋塞米可减少碱性高 K 饮食小鼠中 BK-αβ4 介导的 K 分泌。
DOI：
10.1152/ajprenal.00223.2018
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Sansom,StevenC
中科院分区：
文献类型：
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作者：
Wang,Bangchen;Wang-France,Jun;Li,Huaqing;Sansom,StevenC
特殊的高钾饮食具有心脏保护作用，通常与利尿剂如呋塞米联合使用以治疗高血压。然而，尚不清楚高钾饮食（HK）如何影响利尿剂对肾脏K+处理的作用。呋塞米通过TAL中的Na+-H+交换器3（NHE 3）和远端肾单位中的空泡H+-ATP酶（V-ATP酶）增加酸分泌来酸化尿液。我们以前发现，在HK小鼠中，碱性尿是大电导Ca 2+激活的K+（BK）-αβ4介导的K+分泌所必需的。因此，我们假设呋塞米可通过酸化尿液减少BK-αβ4介导的K+分泌。用呋塞米（饮用水）治疗11天导致野生型（WT）和BK-β4-敲除小鼠（BK-β4-KO）尿液pH值降低，V-ATP酶表达增加，血浆醛固酮水平升高。然而，呋塞米降低了WT的肾脏K+清除率和升高了血浆[K+]，但BK-β4-KO没有。Western blotting和免疫荧光染色结果显示，呋塞米处理可降低皮质BK-β4的表达，减少BK-α在连接小管顶端的定位。在呋塞米水中加入碳酸酐酶抑制剂乙酰唑胺后，尿液pH值沿着恢复，肾脏K+清除率和血浆[K+]恢复至对照水平。乙酰唑胺加呋塞米也恢复了连接小管中BK-β4和BK-α的皮质表达。这些结果表明，在适应HK的小鼠中，呋塞米通过酸化尿液减少BK-αβ4介导的K+分泌。
Special high-K diets have cardioprotective effects and are often warranted in conjunction with diuretics such as furosemide for treating hypertension. However, it is not understood how a high-K diet (HK) influences the actions of diuretics on renal K+handling. Furosemide acidifies the urine by increasing acid secretion via the Na+-H+exchanger 3 (NHE3) in TAL and vacuolar H+-ATPase (V-ATPase) in the distal nephron. We previously found that an alkaline urine is required for large conductance Ca2+-activated K+(BK)-αβ4-mediated K+secretion in mice on HK. We therefore hypothesized that furosemide could reduce BK-αβ4-mediated K+secretion by acidifying the urine. Treating with furosemide (drinking water) for 11 days led to decreased urine pH in both wild-type (WT) and BK-β4-knockout mice (BK-β4-KO) with increased V-ATPase expression and elevated plasma aldosterone levels. However, furosemide decreased renal K+clearance and elevated plasma [K+] in WT but not BK-β4-KO. Western blotting and immunofluorescence staining showed that furosemide treatment decreased cortical expression of BK-β4 and reduced apical localization of BK-α in connecting tubules. Addition of the carbonic anhydrase inhibitor, acetazolamide, to furosemide water restored urine pH along with renal K+clearance and plasma [K+] to control levels. Acetazolamide plus furosemide also restored the cortical expression of BK-β4 and BK-α in connecting tubules. These results indicate that in mice adapted to HK, furosemide reduces BK-αβ4-mediated K+secretion by acidifying the urine.