Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice.
Renal transporter activation during angiotensin-II hypertension is blunted in interferon-γ-/- and interleukin-17A-/- mice.
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DOI：
10.1161/hypertensionaha.114.04975
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发表时间：
2015-03
期刊：
影响因子：
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通讯作者：
McDonough AA
中科院分区：
文献类型：
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作者：
Kamat NV;Thabet SR;Xiao L;Saleh MA;Kirabo A;Madhur MS;Delpire E;Harrison DG;McDonough AA
充足的遗传和生理学证据表明，肾盐处理是血压的关键调节器。研究还确定了免疫系统、T细胞浸润和免疫细胞因子在高血压中的作用。本研究旨在将免疫细胞因子，特别是IFN-γ和IL-17 A，与血管紧张素II（AngII）高血压期间肾脏中的钠转运蛋白调节联系起来。C57 BL/6 J（野生型，WT）小鼠对AngII输注（490 ng/kg/min，2周）有反应，血压升高（至170 mmHg），生理盐水激发的排泄速率显著降低。相比之下，缺乏产生IFN-γ（IFN-γ−/−）或IL-17 A（IL-17 A −/−）能力的小鼠表现出血压的钝性升高（<150 mmHg），并且两种基因型对盐水挑战都保持了基线利尿和利钠反应。沿着远端肾单位，AngII输注增加了WT和IL-17 A −/−小鼠中磷酸化形式的Na-K-2Cl协同转运蛋白、Na-Cl协同转运蛋白和Ste 20/SPS-1相关的富含脯氨酸-丙氨酸激酶的丰度，但在IFN-γ−/−小鼠中没有增加;所有三种基因型的上皮Na通道丰度增加相似。在近端肾单位中，AngII输注显著降低了IL-17 A −/−和IFN-γ−/−中Na/H交换器亚型3和运动肌球蛋白VI的丰度，但不影响WT;所有三种基因型的Na-磷酸盐协同转运蛋白均降低。我们的研究结果表明，在血管紧张素Ⅱ高血压期间，IFN-γ和IL-17 A的产生都干扰了近端小管钠转运中的压力性利钠尿减少，并且IFN-γ的产生是激活远端钠重吸收所必需的。
Ample genetic and physiological evidence establishes that renal salt handling is a critical regulator of blood pressure. Studies also establish a role for the immune system, T-cell infiltration and immune cytokines in hypertension. This study aimed to connect immune cytokines, specifically IFN-γ and IL-17A, to sodium transporter regulation in the kidney during angiotensin II (AngII) hypertension. C57BL/6J (wild type, WT) mice, responded to AngII infusion (490 ng/kg/min, 2 weeks) with a rise in blood pressure (to 170 mmHg) and a significant decrease in the rate of excretion of a saline challenge. In comparison, mice that lacked the ability to produce either IFN-γ (IFN-γ−/−) or IL-17A (IL-17A−/−) exhibited a blunted rise in blood pressure (to <150 mmHg), and both genotypes maintained baseline diuretic and natriuretic responses to a saline challenge. Along the distal nephron, AngII infusion increased abundance of the phosphorylated forms of the Na-K-2Cl cotransporter, Na-Cl cotransporter and Ste20/SPS-1 related proline-alanine rich kinase, in both the WT and IL-17A−/− but not in IFN-γ−/− mice; epithelial Na channel abundance increased similarly in all three genotypes. In the proximal nephron, AngII infusion significantly decreased abundance of Na/H-exchanger isoform 3 and the motor myosin VI in IL-17A−/− and IFN-γ−/− , but not WT; the Na-phosphate cotransporter decreased in all three genotypes. Our results suggest that during AngII hypertension both IFN-γ and IL-17A production interfere with the pressure natriuretic decrease in proximal tubule sodium transport and that IFN-γ production is necessary to activate distal sodium reabsorption.