Local renal circadian clocks control fluid-electrolyte homeostasis and BP.
Local renal circadian clocks control fluid-electrolyte homeostasis and BP.
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DOI：
10.1681/asn.2013060641
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发表时间：
2014-07
期刊：
影响因子：
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通讯作者：
Natsuko Tokonami;D. Mordasini;S. Pradervand;G. Centeno;Céline Jouffe;M. Maillard;O. Bonny;F. Gachon;R. A. Gomez;M. Sequeira-Lopez;D. Firsov
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文献类型：
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作者：
Natsuko Tokonami;D. Mordasini;S. Pradervand;G. Centeno;Céline Jouffe;M. Maillard;O. Bonny;F. Gachon;R. A. Gomez;M. Sequeira-Lopez;D. Firsov
昼夜节律系统在维持体液和电解质平衡以及血压控制中起着至关重要的作用。然而，外周生物钟在这些体内平衡机制中的作用尚不清楚。我们在携带生物钟基因Bmal1条件等位基因并在内源性肾素启动子下表达Cre重组酶的小鼠模型(Bmal1（lox/lox)/Ren1(d)Cre小鼠）中解决了这个问题。对Bmal1(lox/lox)/Ren1(d)Cre小鼠的分析表明，在肾脏中切除了固定的Bmal1等位基因。在肾脏中，肾小球旁器和集合管的肾素分泌颗粒细胞中缺乏BMAL1蛋白的表达。BMAL1表达在髓质厚升肢部分减少。功能分析显示，Bmal1(lox/lox)/Ren1(d)Cre小鼠表现出多种异常，包括尿量增加、尿钠排泄昼夜节律改变、GFR升高、血浆醛固酮水平显著降低。这些变化伴随着血压的降低。这些结果表明，局部肾脏生物钟控制体液和血压稳态。
The circadian timing system is critically involved in the maintenance of fluid and electrolyte balance and BP control. However, the role of peripheral circadian clocks in these homeostatic mechanisms remains unknown. We addressed this question in a mouse model carrying a conditional allele of the circadian clock gene Bmal1 and expressing Cre recombinase under the endogenous Renin promoter (Bmal1(lox/lox)/Ren1(d)Cre mice). Analysis of Bmal1(lox/lox)/Ren1(d)Cre mice showed that the floxed Bmal1 allele was excised in the kidney. In the kidney, BMAL1 protein expression was absent in the renin-secreting granular cells of the juxtaglomerular apparatus and the collecting duct. A partial reduction of BMAL1 expression was observed in the medullary thick ascending limb. Functional analyses showed that Bmal1(lox/lox)/Ren1(d)Cre mice exhibited multiple abnormalities, including increased urine volume, changes in the circadian rhythm of urinary sodium excretion, increased GFR, and significantly reduced plasma aldosterone levels. These changes were accompanied by a reduction in BP. These results show that local renal circadian clocks control body fluid and BP homeostasis.