Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA.
Kidney Int. 2010 Mar;77(6):500-8. doi: 10.1038/ki.2009.483. Epub 2009 Dec 23.
Peristaltic waves of the ureteric smooth muscles move urine down from the kidney, a process that is commonly defective in congenital diseases. To study the mechanisms that control the initiation and direction of contractions, we used video microscopy and optical mapping techniques and found that electrical and contractile waves began in a region where the renal pelvis joined the connective tissue core of the kidney. Separation of this pelvis-kidney junction from more distal urinary tract segments prevented downstream peristalsis, indicating that it housed the trigger for peristalsis. Moreover, cells in the pelvis-kidney junction were found to express isoform 3 of the hyperpolarization-activated cation on channel family known to be required for initiating electrical activity in the brain and heart. Immunocytochemical and real-time PCR analyses found that hyperpolarization-activated cation-3 is expressed at the pelvis-kidney junction where electrical excitation and contractile waves originate. Inhibition of this channel caused a loss of electrical activity at the pelvis-kidney junction and randomized the origin of electrical activity in the urinary tract, thus markedly perturbing contractions. Collectively, our study demonstrates that hyperpolarization-activated cation-3 channels play a fundamental role in coordinating proximal-to-distal peristalsis of the upper urinary tract. This provides insight into the genetic causes of common inherited urinary tract disorders such as reflux and obstruction.
输尿管平滑肌的蠕动波将尿液从肾脏向下移动，这一过程在先天性疾病中通常存在缺陷。为了研究控制收缩起始和方向的机制，我们使用视频显微镜和光学映射技术发现，电和收缩波首先出现在肾盂与肾脏结缔组织核心相连的区域。将肾盂-肾脏交界处与更远端的尿路段分离，可防止下游蠕动，表明其包含蠕动的触发点。此外，在肾盂-肾脏交界处的细胞中发现表达已知在大脑和心脏中启动电活动所必需的超极化激活阳离子通道家族的同工型 3。免疫细胞化学和实时 PCR 分析发现，超极化激活阳离子-3 在电兴奋和收缩波起源的肾盂-肾脏交界处表达。该通道的抑制导致肾盂-肾脏交界处的电活动丧失，并使尿路中电活动的起源随机化，从而显著扰乱收缩。总的来说，我们的研究表明，超极化激活阳离子-3 通道在协调上尿路的近-远蠕动中起基础性作用。这为常见遗传性尿路疾病（如反流和梗阻）的遗传原因提供了深入了解。
