Bradykinin acutely inhibits activity of the epithelial Na+ channel in mammalian aldosterone-sensitive distal nephron.
Bradykinin acutely inhibits activity of the epithelial Na+ channel in mammalian aldosterone-sensitive distal nephron.
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DOI：
10.1152/ajprenal.00606.2010
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发表时间：
2011-05
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影响因子：
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通讯作者：
Oleg L. Zaika;M. Mamenko;R. O'neil;O. Pochynyuk
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作者：
Oleg L. Zaika;M. Mamenko;R. O'neil;O. Pochynyuk
肾脏激肽释放酶-激肽系统的激活导致尿钠排泄和利尿，提示其可能在肾小管钠转运调节中起作用。在这里，我们使用膜片钳电生理学直接评估缓激肽（BK）对上皮Na（+）通道（ENaC）活性的影响，在新鲜分离的分裂开放的小鼠醛固酮敏感性远端肾单位（ASDNs）。BK通过以剂量依赖性和可逆的方式降低通道开放概率（P（o））来急性抑制ENaC活性。用艾替班特（HOE-140）抑制B2受体可消除BK对ENaC的作用。相反，用选择性激动剂Lys-des-Arg（9）-BK激活B1受体，不能再现BK对ENaC的作用。这与B2受体在介导BK信号传导至ENaC中发挥关键作用一致。当G（q/11）被G p拮抗剂2A抑制时，BK对ENaC P（o）的影响不大。此外，抑制磷脂酶C（PLC）与U 73122，但不饱和的细胞cAMP水平与膜渗透性的不可水解的cAMP类似物8-cpt-cAMP，防止BK行动ENaC活动。这表明BK刺激B2受体，随后激活G（q/11）-PLC信号级联，从而急性抑制ENaC活性。BK信号传导的激活急性耗尽顶端PI（4，5）P（2）水平。然而，毒胡萝卜素抑制内质网的Ca（2+）泵SERCA并不能阻止BK信号传导至ENaC。此外，咖啡因，虽然产生类似的上升[Ca（2+）]（i）作为对BK刺激的反应，但不能概括BK对ENaC的作用。因此，我们得出结论，BK通过刺激B2受体和随后的PI（4，5）P（2）耗竭而不是[Ca（2+）]（i）增加来急性抑制哺乳动物ASDN中的ENaC P（o）。
Activation of the renal kallikrein-kinin system results in natriuresis and diuresis, suggesting its possible role in renal tubular sodium transport regulation. Here, we used patch-clamp electrophysiology to directly assess the effects of bradykinin (BK) on the epithelial Na(+) channel (ENaC) activity in freshly isolated split-opened murine aldosterone-sensitive distal nephrons (ASDNs). BK acutely inhibits ENaC activity by reducing channel open probability (P(o)) in a dose-dependent and reversible manner. Inhibition of B2 receptors with icatibant (HOE-140) abolished BK actions on ENaC. In contrast, activation of B1 receptors with the selective agonist Lys-des-Arg(9)-BK failed to reproduce BK actions on ENaC. This is consistent with B2 receptors playing a critical role in mediating BK signaling to ENaC. BK has little effect on ENaC P(o) when G(q/11) was inhibited with Gp antagonist 2A. Moreover, inhibition of phospholipase C (PLC) with U73122, but not saturation of cellular cAMP levels with the membrane-permeable nonhydrolysable cAMP analog 8-cpt-cAMP, prevents BK actions on ENaC activity. This argues that BK stimulates B2 receptors with subsequent activation of G(q/11)-PLC signaling cascade to acutely inhibit ENaC activity. Activation of BK signaling acutely depletes apical PI(4,5)P(2) levels. However, inhibition of Ca(2+) pump SERCA of the endoplasmic reticulum with thapsigargin does not prevent BK signaling to ENaC. Furthermore, caffeine, while producing a similar rise in [Ca(2+)](i) as in response to BK stimulation, fails to recapitulate BK actions on ENaC. Therefore, we concluded that BK acutely inhibits ENaC P(o) in mammalian ASDN via stimulation of B2 receptors and following depletion of PI(4,5)P(2), but not increases in [Ca(2+)](i).