Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.
Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.
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DOI：
10.1161/hypertensionaha.112.200469
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发表时间：
2012-11
期刊：
影响因子：
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通讯作者：
Pochynyuk O
中科院分区：
文献类型：
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作者：
Mamenko M;Zaika O;Doris PA;Pochynyuk O
我们最近发现缓激肽（BK）通过B2 R-Gq/11-PLC途径直接抑制上皮Na+通道（ENaC）的活性。在这项研究中，我们利用基因工程小鼠缺乏缓激肽受体（B1 R，B2 R-/-），以探测BK级联在天然组织，醛固酮敏感性远端肾单位（ASDN）的ENaC的调节中的生理作用。在正常钠摄入量（0.32%Na+）下，与WT小鼠相比，B1 R、B2 R-/-小鼠中的ENaC开放概率（Po）适度升高。这种差异在Na+摄入量升高（2%Na+）时增大，在Na+限制（<0.01%Na+）时消失。醋酸脱氧皮质酮（DOCA）饱和全身盐皮质激素状态同样增加ENaC活性在两种小鼠品系表明BK对ENaC的影响是独立的醛固酮。血管紧张素转换酶（ACE）是BK降解的主要途径。用卡托普利（30 mg/kgBW，持续7天）全身抑制ACE可显著降低WT小鼠的ENaC活性和Po，但这种作用在B1 R，B2 R-/-小鼠中减弱。在细胞水平，急性卡托普利（100 μM）处理敏化BK信号级联反应，大大增强了100 nM BK对ENaC的抑制作用。我们的结论是，BK级联在钝化ENaC活性方面具有其自身的特定作用，特别是在钠摄入量升高的条件下。ASDN中BK信号的增强抑制了ENaC介导的Na+重吸收，这有助于ACE抑制的利钠和抗高血压作用。
We have recently documented that Bradykinin (BK) directly inhibits activity of the Epithelial Na+ Channel (ENaC) via B2R-Gq/11-PLC pathway. In this study, we took advantage of mice genetically engineered to lack bradykinin receptors (B1R,B2R-/-) to probe a physiological role of BK cascade in regulation of ENaC in native tissue, aldosterone-sensitive distal nephron (ASDN). Under normal sodium intake (0.32%Na+), ENaC open probability (Po) was modestly elevated in B1R,B2R-/- mice compared to WT mice. This difference is augmented during elevated Na+ intake (2%Na+) and negated during Na+ restriction (<0.01%Na+). Saturation of systemic mineralocorticoid status with deoxycorticosterone acetate (DOCA) similarly increased ENaC activity in both mouse strains suggesting that the effect of BK on ENaC is independent of aldosterone. It is accepted that angiotensin converting enzyme (ACE) represents the major pathway of BK degradation. Systemic inhibition of ACE with captopril (30 mg/kgBW for 7 days) significantly decreases ENaC activity and Po in WT mice but this effect is diminished in B1R,B2R-/- mice. At the cellular level, acute captopril (100 μM) treatment sensitized BK signaling cascade and greatly potentiated the inhibitory effect of 100 nM BK on ENaC. We concluded that BK cascade has its own specific role in blunting ENaC activity particularly under conditions of elevated sodium intake. Augmentation of BK signaling in the ASDN inhibits ENaC-mediated Na+-reabsorption contributing to the natriuretic and antihypertensive effects of ACE inhibition.