Park Jennifer, Kemp Brandon A, Howell Nancy L, Gildea John J, Keller Susanna R, Carey Robert M
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1414, USA.
Hypertension. 2008 Feb;51(2):494-9. doi: 10.1161/HYPERTENSIONAHA.107.103036. Epub 2008 Jan 2.
Extracellular renal interstitial (RI) cGMP modulates NO- and pressure-induced natriuresis in vivo in the rat. The present study objective was to test the hypothesis that an intact microtubulin network is required for transport of cGMP from intracellular sites into the extracellular compartment in vivo and that this transport is required for natriuresis induced by NO and increased renal perfusion pressure. After a 1-hour control period, uninephrectomized rats received an RI infusion of NO donor S-nitroso-N-acetylpenicillamine (SNAP), SNAP+microtubule inhibitor nocodazole (NOC), SNAP+NOC+cGMP, or NOC alone for 2 consecutive 1-hour collection periods. SNAP alone increased RI cGMP (P<0.05 during both experimental periods) and urinary sodium excretion (P<0.05 at 1 hour and P<0.005 at 2 hours). In contrast, when SNAP+NOC were coinfused, there was no increase in either RI cGMP or urinary sodium excretion. However, when cGMP was coinfused with SNAP+NOC, the natriuretic response to SNAP was fully restored. Similarly, NOC abolished SNAP-induced increases in the fractional excretion of Na(+) and Li(+). NOC also prevented the increase in both RI cGMP and natriuresis engendered by raising renal perfusion pressure in uninephrectomized rats, and pressure-natriuresis was re-established by coadministration of RI cGMP. As demonstrated by confocal microscopy after in vivo renal perfusion fixation, beta-tubulin was disrupted in renal cortical nephrons of kidneys infused intrarenally with NOC. These observations indicate that a functioning microtubulin network is required for the transport of cGMP into the extracellular space to modulate NO- and pressure-induced natriuresis.
细胞外肾间质（RI）中的环磷酸鸟苷（cGMP）可在大鼠体内调节一氧化氮（NO）和压力诱导的利钠作用。本研究的目的是验证以下假设：完整的微管蛋白网络是体内cGMP从细胞内位点转运到细胞外区室所必需的，并且这种转运是NO和肾灌注压升高诱导利钠作用所必需的。在1小时的对照期后，单侧肾切除的大鼠在连续2个1小时的收集期内接受RI输注，分别为NO供体S-亚硝基-N-乙酰青霉胺（SNAP）、SNAP+微管抑制剂诺考达唑（NOC）、SNAP+NOC+cGMP或单独的NOC。单独使用SNAP可增加RI中的cGMP（两个实验期内P<0.05）和尿钠排泄（1小时时P<0.05，2小时时P<0.005）。相比之下，当同时输注SNAP+NOC时，RI中的cGMP或尿钠排泄均未增加。然而，当cGMP与SNAP+NOC同时输注时，对SNAP的利钠反应完全恢复。同样，NOC消除了SNAP诱导的Na(+)和Li(+)分数排泄增加。NOC还可防止单侧肾切除大鼠因肾灌注压升高而导致的RI中cGMP和利钠作用增加，并且通过同时给予RI cGMP可重建压力利钠作用。如体内肾灌注固定后的共聚焦显微镜所示，向肾内输注NOC的肾脏的肾皮质肾单位中的β-微管蛋白被破坏。这些观察结果表明，一个功能正常的微管蛋白网络是cGMP转运到细胞外空间以调节NO和压力诱导的利钠作用所必需的。
