Mamenko Mykola V, Boukelmoune Nabila, Tomilin Viktor N, Zaika Oleg L, Jensen V Behrana, O'Neil Roger G, Pochynyuk Oleh M
Department of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Department of Integrative Biology and Pharmacology, the University of Texas Health Science Center at Houston, Houston, Texas, USA.
Kidney Int. 2017 Jun;91(6):1398-1409. doi: 10.1016/j.kint.2016.12.010. Epub 2017 Feb 7.
To maintain potassium homeostasis, kidneys exert flow-dependent potassium secretion to facilitate kaliuresis in response to elevated dietary potassium intake. This process involves stimulation of calcium-activated large conductance maxi-K (BK) channels in the distal nephron, namely the connecting tubule and the collecting duct. Recent evidence suggests that the TRPV4 channel is a critical determinant of flow-dependent intracellular calcium elevations in these segments of the renal tubule. Here, we demonstrate that elevated dietary potassium intake (five percent potassium) increases renal TRPV4 mRNA and protein levels in an aldosterone-dependent manner and causes redistribution of the channel to the apical plasma membrane in native collecting duct cells. This, in turn, leads to augmented TRPV4-mediated flow-dependent calcium ion responses in freshly isolated split-opened collecting ducts from mice fed the high potassium diet. Genetic TRPV4 ablation greatly diminished BK channel activity in collecting duct cells pointing to a reduced capacity to excrete potassium. Consistently, elevated potassium intake induced hyperkalemia in TRPV4 knockout mice due to deficient renal potassium excretion. Thus, regulation of TRPV4 activity in the distal nephron by dietary potassium is an indispensable component of whole body potassium balance.
为维持钾稳态，肾脏会根据饮食中钾摄入量的增加，通过流量依赖性钾分泌来促进尿钾排泄。这一过程涉及刺激远端肾单位（即连接小管和集合管）中的钙激活大电导钙激活钾（BK）通道。最近的证据表明，瞬时受体电位香草酸亚型4（TRPV4）通道是肾小管这些节段中流量依赖性细胞内钙升高的关键决定因素。在此，我们证明，饮食中钾摄入量增加（5%钾）会以醛固酮依赖的方式增加肾脏TRPV4的mRNA和蛋白质水平，并导致该通道在天然集合管细胞的顶端质膜重新分布。这反过来又导致来自高钾饮食喂养小鼠的新鲜分离的开放集合管中TRPV4介导的流量依赖性钙离子反应增强。基因敲除TRPV4会大大降低集合管细胞中的BK通道活性，表明钾排泄能力下降。同样，由于肾脏钾排泄不足，高钾饮食会导致TRPV4基因敲除小鼠出现高钾血症。因此，饮食钾对远端肾单位中TRPV4活性的调节是全身钾平衡不可或缺的组成部分。
