Department of Ophthalmology, Weill Cornell Medical College, Margaret Dyson Vision Research Institute, New York, New York.
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
Curr Opin Nephrol Hypertens. 2019 Sep;28(5):474-480. doi: 10.1097/MNH.0000000000000531.
The apical Na/K/2Cl cotransporter (NKCC2) mediates NaCl reabsorption by the thick ascending limb, contributing to maintenance of blood pressure (BP). Despite effective NKCC2 inhibition by loop diuretics, these agents are not viable for long-term management of BP due to side effects. Novel molecular mechanisms that control NKCC2 activity reveal an increasingly complex picture with interacting layers of NKCC2 regulation. Here, we review the latest developments that shine new light on NKCC2-mediated control of BP and potential new long-term therapies to treat hypertension.
Emerging molecular NKCC2 regulators, often binding partners, reveal a complex overlay of interacting mechanisms aimed at fine tuning NKCC2 activity. Different factors achieve this by shifting the balance between trafficking steps like exocytosis, endocytosis, recycling and protein turnover, or by balancing phosphorylation vs. dephosphorylation. Further molecular details are also emerging on previously known pathways of NKCC2 regulation, and recent in-vivo data continues to place NKCC2 regulation at the center of BP control.
Several layers of emerging molecular mechanisms that control NKCC2 activity may operate simultaneously, but they can also be controlled independently. This provides an opportunity to identify new pharmacological targets to fine-tune NKCC2 activity for BP management.
目的综述：顶端钠钾 2 氯协同转运蛋白（NKCC2）通过升支粗段介导 NaCl 的重吸收，有助于维持血压（BP）。尽管袢利尿剂能有效抑制 NKCC2，但由于其副作用，这些药物不适用于长期血压管理。控制 NKCC2 活性的新分子机制揭示了一个日益复杂的画面，其中 NKCC2 的调节存在相互作用的层次。在此，我们综述了最新的研究进展，这些进展为 NKCC2 介导的 BP 控制和治疗高血压的潜在新的长期治疗方法提供了新的视角。
最新发现：新兴的 NKCC2 分子调节因子，通常是结合伴侣，揭示了相互作用的复杂机制，旨在精细调节 NKCC2 的活性。不同的因素通过改变胞吐、内吞、循环和蛋白周转等转运步骤之间的平衡，或者通过平衡磷酸化与去磷酸化来实现这一点。NKCC2 调节的先前已知途径也出现了更多的分子细节，最近的体内数据继续将 NKCC2 调节置于 BP 控制的中心。
总结：控制 NKCC2 活性的几个新兴分子机制层可能同时起作用，但也可以独立控制。这为识别新的药理学靶点以微调 NKCC2 活性用于 BP 管理提供了机会。
