Di Giusto Gisela, Anzai Naohiko, Endou Hitoshi, Torres Adriana M
Farmacología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Rosario, Argentina.
Pharmacology. 2008;81(2):127-36. doi: 10.1159/000110555. Epub 2007 Oct 30.
BACKGROUND/AIMS: The knowledge of molecular mechanisms determining drug pharmacokinetics in pathological states is relevant for the development of new therapeutic approaches. This study was undertaken to evaluate the cortical renal blood flow (cRBF) and the renal protein expression of the organic anion transporters (OAT1 and OAT3) in association with the elimination of organic anions in an early stage of renal ischemia-reperfusion.
Ischemic acute renal failure (ARF) was induced in adult male Wistar rats by occlusion of both renal pedicles during 60 min, followed by 60 min of reperfusion (ARF group). Pair-fed sham-operated rats served as controls. The renal protein expression of OAT1 and OAT3 was evaluated by immunohistochemistry techniques and by Western blotting in renal cortex homogenates and in basolateral plasma membranes. A pharmacokinetic study of p-aminohippurate (PAH, a prototypical organic anion) was performed. cRBF was determined using fluorescent microspheres.
ARF rats displayed a significant decrease in systemic clearance and in renal excretion of PAH. OAT1 and OAT3 protein abundance showed a statistically significant reduction both in homogenates and in basolateral plasma membranes from ARF rats. Immunohistochemical studies confirmed the changes in the cortical renal expression of these transporters. ARF animals also showed a decrease in cRBF.
The decrease in PAH elimination observed in an early stage of renal ischemia-reperfusion in male Wistar rats might be explained by the sum of the lower OAT1 and OAT3 expression in renal basolateral plasma membranes plus the decrease in cRBF. These findings might have significant implications in the development of novel pharmacological strategies to be applied in the initial stages of ischemic ARF.
背景/目的：了解决定病理状态下药物药代动力学的分子机制，对于开发新的治疗方法具有重要意义。本研究旨在评估肾缺血再灌注早期皮质肾血流量（cRBF）以及有机阴离子转运体（OAT1和OAT3）的肾蛋白表达与有机阴离子消除之间的关系。
成年雄性Wistar大鼠通过双侧肾蒂阻断60分钟诱导缺血性急性肾衰竭（ARF），随后再灌注60分钟（ARF组）。配对喂养的假手术大鼠作为对照。通过免疫组织化学技术以及肾皮质匀浆和基底外侧质膜中的蛋白质免疫印迹法评估OAT1和OAT3的肾蛋白表达。进行了对氨基马尿酸（PAH，一种典型的有机阴离子）的药代动力学研究。使用荧光微球测定cRBF。
ARF大鼠的全身清除率和PAH的肾排泄量显著降低。ARF大鼠的匀浆和基底外侧质膜中OAT1和OAT3蛋白丰度均显示出统计学上的显著降低。免疫组织化学研究证实了这些转运体在肾皮质表达的变化。ARF动物的cRBF也有所降低。
雄性Wistar大鼠肾缺血再灌注早期观察到的PAH消除减少，可能是由于肾基底外侧质膜中OAT1和OAT3表达降低以及cRBF减少共同作用的结果。这些发现可能对开发应用于缺血性ARF初始阶段的新型药理学策略具有重要意义。
