Department of Nephrology, Clinical Sciences Lund, Lund University , Lund , Sweden.
Department of Anesthesiology and Intensive Care, Clinical Sciences Lund, Lund University , Lund , Sweden.
Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F445-F453. doi: 10.1152/ajprenal.00610.2017. Epub 2018 Feb 21.
It is well known that proteinuria following urinary tract obstruction is mainly of a tubular nature. However, it is unknown whether there are also changes in glomerular permeability. In this study, we compared glomerular sieving coefficients (θ) of polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400 following a 120- or 180-min unilateral ureteral obstruction (UUO) in anesthetized Sprague-Dawley rats. Samples were collected from the obstructed kidney at 5, 15, and 30 min postrelease and analyzed by means of high-pressure size-exclusion chromatography. After 120-min UUO, mean θ for Ficoll was increased ( P < 0.01) from 2.2 ± 0.5 × 10 (baseline) to 10.6 ± 10 × 10 15 min postrelease (highest value). After 180-min UUO, mean θ for Ficoll was further increased ( P < 0.001) from 1.4 ± 0.5 × 10 (baseline) to 40 ± 10 × 10 at 5 min postrelease (highest value). Administration of a reactive oxygen species (ROS) scavenger (Tempol; 1 mg·kg·min) partly abrogated the permeability effects following 120-min UUO but not after 180 min. Moreover, administration of the RhoA kinase inhibitor Y-27632, the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester, or Rac-1 inhibition did not ameliorate glomerular hyperpermeability following 180-min UUO. We show, for the first time, that acute UUO results in marked elevations in glomerular permeability. In addition, our data suggest a time-dependent pathophysiology of UUO-induced hyperpermeability, where reactive oxygen species generation may play an important role in the early stages.
众所周知，尿路梗阻后的蛋白尿主要为肾小管性质。然而，肾小球通透性是否也发生变化尚不清楚。在这项研究中，我们比较了麻醉 Sprague-Dawley 大鼠单侧输尿管梗阻（UUO）120 或 180 分钟后聚分散性异硫氰酸荧光素（FITC）-Ficoll 70/400 的肾小球筛系数（θ）。在释放后 5、15 和 30 分钟从梗阻肾脏收集样本，并通过高压尺寸排除色谱法进行分析。UUO 120 分钟后，Ficoll 的平均θ值增加（P < 0.01），从释放前的 2.2±0.5×10 15 min 升至 10.6±10×10 （最高值）。UUO 180 分钟后，Ficoll 的平均θ值进一步增加（P < 0.001），从基线的 1.4±0.5×10升至释放后 5 min 的 40±10×10 （最高值）。活性氧（ROS）清除剂（Tempol；1 mg·kg·min）的给药部分阻断了 120 分钟 UUO 后的通透性效应，但在 180 分钟后没有阻断。此外，RhoA 激酶抑制剂 Y-27632、一氧化氮合酶抑制剂 N-硝基-L-精氨酸甲酯或 Rac-1 抑制不能改善 180 分钟 UUO 后的肾小球高通透性。我们首次表明，急性 UUO 导致肾小球通透性显著升高。此外，我们的数据表明 UUO 诱导的高通透性存在时间依赖性病理生理学，其中活性氧的产生可能在早期发挥重要作用。
