NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension.
NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension.
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DOI：
10.1523/jneurosci.1346-12.2012
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发表时间：
2012-06-20
期刊：
影响因子：
--
通讯作者：
Pan HL
中科院分区：
文献类型：
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作者：
Ye ZY;Li DP;Byun HS;Li L;Pan HL
高血压是冠状动脉疾病、中风和肾衰竭的主要危险因素。然而，大多数高血压患者的病因尚不清楚。下丘脑室旁核（PVN）交感神经冲动的增强在高血压的发生发展中起着重要作用。脑中的Na+-K+-2Cl−协同转运蛋白-1（NKCC 1）在维持氯稳态和GABAA受体介导的神经元反应中发挥重要作用。在这里，我们提出了新的证据表明，GABA逆转电位（EGABA）的室旁核前交感神经元经历了去极化转变，减少GABA抑制自发性高血压大鼠（SHR）。抑制NKCC 1，而不是KCC 2，使GABA正常化，并恢复GABA对SHR PVN神经元的抑制。在SHR中，室旁核中NKCC 1的mRNA和蛋白水平显著增加，而KCC 2则没有，并且质膜上的NKCC 1蛋白高度糖基化。抑制NKCC 1 N-糖基化恢复SHR中室旁核前交感神经元的GABA和GABA能抑制。此外，NKCC 1抑制显著降低交感神经血管紧张度，并增强对SHR PVN中GABAA受体激活的交感神经抑制反应。这些发现表明，NKCC 1活性和糖基化的增加会破坏氯稳态并损害PVN中的突触抑制，从而增强高血压中的交感神经驱动。这些信息大大提高了我们对高血压发病机制的认识，有助于设计更好的神经源性高血压治疗策略。
Hypertension is a major risk factor for coronary artery disease, stroke, and kidney failure. However, the etiology of hypertension in most patients is poorly understood. Increased sympathetic drive emanating from the hypothalamic paraventricular nucleus (PVN) plays a major role in the development of hypertension. Na+-K+-2Cl− cotransporter-1 (NKCC1) in the brain is critically involved in maintaining chloride homeostasis and in neuronal responses mediated by GABAA receptors. Here we present novel evidence that the GABA reversal potential (EGABA) of PVN presympathetic neurons undergoes a depolarizing shift that diminishes GABA inhibition in spontaneously hypertensive rats (SHRs). Inhibition of NKCC1, but not KCC2, normalizes EGABA and restores GABA inhibition of PVN neurons in SHRs. The mRNA and protein levels of NKCC1, but not KCC2, in the PVN are significantly increased in SHRs, and the NKCC1 proteins on the plasma membrane are highly glycosylated. Inhibiting NKCC1 N-glycosylation restores EGABA and GABAergic inhibition of PVN presympathetic neurons in SHRs. Furthermore, NKCC1 inhibition significantly reduces the sympathetic vasomotor tone and augments the sympathoinhibitory responses to GABAA receptor activation in the PVN in SHRs. These findings suggest that increased NKCC1 activity and glycosylation disrupts chloride homeostasis and impairs synaptic inhibition in the PVN to augment the sympathetic drive in hypertension. This information greatly improves our understanding of the pathogenesis of hypertension and helps to design better treatment strategies for neurogenic hypertension.