Canonica Jérémie, Frateschi Simona, Boscardin Emilie, Ebering Anna, Sergi Chloé, Jäger Yannick, Peyrollaz Thibaud, Mérillat Anne-Marie, Maillard Marc, Klusonova Petra, Odermatt Alex, Koesters Robert, Debonneville Anne, Staub Olivier, Verouti Sophia N, Hummler Edith
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
National Centre of Competence in Research "Kidney.CH", Lausanne, Switzerland.
Front Physiol. 2019 Aug 14;10:989. doi: 10.3389/fphys.2019.00989. eCollection 2019.
Chronic glucocorticoid infusion impairs NCC activity and induces a non-dipping profile in mice, suggesting that glucocorticoids are essential for daily blood pressure variations. In this paper, we studied mice lacking the renal tubular glucocorticoid receptor (GR) in adulthood (GR knockouts, ). Upon standard salt diet, mice grow normally, but show reduced NCC activity despite normal plasma aldosterone levels. Following diet switch to low sodium, mice exhibit a transient but significant reduction in the activity of NCC and expression of NHE3 and NKCC2 accompanied by significant increased Spak activity. This is followed by transiently increased urinary sodium excretion and higher plasma aldosterone concentrations. Plasma corticosterone levels and 11βHSD2 mRNA expression and activity in the whole kidney remain unchanged. High salt diet does not affect whole body Na and/or K balance and NCC activity is not reduced, but leads to a significant increase in diastolic blood pressure dipping in mice. When high sodium treatment is followed by 48 h of darkness, NCC abundance is reduced in knockout mice although activity is not different. Our data show that upon Na restriction renal tubular GR-deficiency transiently affects Na handling and transport pathways. Overall, upon standard, low Na and high Na diet exposure Na and K balance is maintained as evidenced by normal plasma and urinary Na and K and aldosterone concentrations.
慢性糖皮质激素输注会损害小鼠的NCC活性并诱导非勺型血压模式，这表明糖皮质激素对每日血压变化至关重要。在本文中，我们研究了成年期缺乏肾小管糖皮质激素受体（GR）的小鼠（GR基因敲除小鼠）。在标准盐饮食条件下，GR基因敲除小鼠生长正常，但尽管血浆醛固酮水平正常，其NCC活性仍降低。在饮食转换为低钠后，GR基因敲除小鼠的NCC活性、NHE3和NKCC2的表达出现短暂但显著的降低，同时Spak活性显著增加。随后尿钠排泄短暂增加，血浆醛固酮浓度升高。血浆皮质酮水平以及全肾中11βHSD2 mRNA的表达和活性保持不变。高盐饮食不影响全身钠和/或钾平衡，NCC活性也未降低，但会导致GR基因敲除小鼠的舒张压勺型现象显著增加。当高钠处理后接着48小时黑暗处理时，基因敲除小鼠的NCC丰度降低，尽管活性没有差异。我们的数据表明，在钠限制条件下，肾小管GR缺乏会短暂影响钠的处理和转运途径。总体而言，在标准、低钠和高钠饮食暴露后，血浆和尿液中的钠、钾以及醛固酮浓度正常，表明钠和钾平衡得以维持。
