Reversible angiotensin II-mediated albuminuria in rat kidneys is dynamically associated with cytoskeletal organization.
Reversible angiotensin II-mediated albuminuria in rat kidneys is dynamically associated with cytoskeletal organization.
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DOI：
10.1159/000068528
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发表时间：
2003-02-01
期刊：
影响因子：
2.5
通讯作者：
Comper, Wayne D.
中科院分区：
文献类型：
--
作者：
Clavant, Steven P.;Forbes, Josephine M.;Comper, Wayne D.
血管紧张素II（ANG II）与正常肾功能密切相关，并且估计在肾小管内以6-10 nM的正常生理范围存在。肾内血管紧张素II可能发挥肾脏疾病的潜在作用进行了评估，通过灌注离体大鼠肾脏或没有多余的肾小管内水平的血管紧张素II，这可能会模仿在病理条件下的肾内RAS的变化。通过渗透泵向大鼠输注ANG II，还测定了增加全身ANG II的作用。在离体灌注肾，ANG II显着和特异性增加了白蛋白的清除率到临床水平，通过使用放射性标记的白蛋白测定。这种效应是可逆的，因为从灌注液中去除ANG II会导致白蛋白清除率降低至ANG II暴露前水平。通过36 ANG Ficoll和免疫球蛋白G的清除率分数测定，白蛋白清除率分数的增加与肾脏血流动力学变化或肾小球通透性变化无关。免疫化学分析使用抗α-微管蛋白抗体灌注肾切片显示，ANG II引起显着的破坏肾小管上皮细胞骨架成分，通过拆卸和重组的α-微管蛋白。这种破坏是可逆的。在体内，渗透泵输送ANG II在较低的有效剂量引起蛋白尿（双缩脲）和白蛋白尿（放射免疫测定）的大鼠，早在2天后植入泵。这些结果表明，血管紧张素II可可逆地诱导临床水平的白蛋白尿。这些数据表明肾小管和肾小管腔内ANG II浓度在白蛋白的肾脏处理中具有重要作用。
Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exist at a normal physiological range of 6-10 nM within the renal tubules. The potential role that intrarenal ANG II may play in renal disease was assessed by perfusing isolated rat kidneys with or without excess intratubular levels of ANG II, which may mimic changes in the intrarenal RAS under pathological conditions. The effects of increased systemic ANG II were also determined by infusing rats with ANG II by osmotic pump. In isolated perfused kidneys, ANG II significantly and specifically increased the fractional clearance of albumin to clinical levels, as determined by using radiolabelled albumin. This effect was reversible, as removing ANG II from the perfusate caused the albumin fractional clearance to decrease to pre-ANG II exposure levels. The increase in fractional clearance of albumin was not correlated with renal hemodynamic changes, nor glomerular permeability alterations as measured by the fractional clearance of 36 ANG Ficoll and immunoglobulin G. Immunochemical analysis using anti-alpha-tubulin antibody of perfused kidney sections revealed that ANG II caused a marked disruption of tubular epithelial cytoskeletal components, through disassembly and reorganization of alpha-tubulin. This disruption was reversible. In vivo, osmotic pump delivery of ANG II at less potent dosage caused a proteinuria (Biuret) and an albuminuria (radioimmunoassay) in rats, from as early as 2 days after pump implantation. These results demonstrate that ANG II may reversibly induce clinical levels of albuminuria. These data point to an important role for renal tubules and the intratubular lumen concentrations of ANG II in the renal processing of albumin.