Oat1/3 restoration protects against renal damage after ischemic AKI.
Oat1/3 restoration protects against renal damage after ischemic AKI.
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DOI：
10.1152/ajprenal.00160.2014
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发表时间：
2015-02
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通讯作者：
R. Schneider;M. Meusel;B. Betz;C. Held;K. Möller-Ehrlich;Maike Büttner-Herold;Christoph Wanner
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作者：
R. Schneider;M. Meusel;B. Betz;C. Held;K. Möller-Ehrlich;Maike Büttner-Herold;Christoph Wanner
肾缺血再灌注 (I/R) 损伤后，PGE2 会降低近端肾小管有机阴离子转运蛋白 Oat1 和 Oat3 的表达。我们假设 Oat1/3 表达受损与 I/R 损伤后肾功能恶化具有决定性作用。因此，我们给予丙磺舒，它阻断近端肾小管吲哚美辛的摄取，以消除吲哚美辛介导的 Oat1/3 调节恢复及其对肾功能和形态结果的影响。通过双侧肾动脉夹闭 45 分钟并随访 24 小时，诱导大鼠缺血性急性肾损伤 (iAKI)。缺血结束时腹膜内（ip）给予低剂量吲哚美辛（1 mg/kg）。 20分钟后，腹腔注射丙磺舒(50mg/kg)。吲哚美辛恢复了 Oat1/3 的表达、PAH 净分泌和 PGE2 清除。此外，吲哚美辛改善了肾功能（通过肾小球滤过率（GFR）测量）、肾灌注（通过校正的 PAH 清除率确定）和形态学，同时减少肾皮质细胞凋亡和一氧化氮的产生。值得注意的是，吲哚美辛不影响肾脏的炎症参数（例如单核细胞趋化蛋白-1、ED1+细胞）。另一方面，丙磺舒阻断了吲哚美辛诱导的 Oat1/3 恢复，而且消除了所有有益作用。我们的研究表明，低剂量吲哚美辛对 iAKI 的有益作用不是由于其抗炎功效，而是与其对 Oat1/3 表达和/或一般肾功能的恢复相反。抑制近端肾小管吲哚美辛摄取可通过重置 PGE2 介导的 Oat1/3 损伤来消除吲哚美辛的有益作用，从而重建肾损伤。这为 Oat1/3 在 iAKI 后诱导肾损伤的新模型中的机制作用提供了证据。
Expression of proximal tubular organic anion transporters Oat1 and Oat3 is reduced by PGE2 after renal ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered probenecid, which blocks proximal tubular indomethacin uptake, to abolish the indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of ischemia. Probenecid (50 mg/kg) was administered ip 20 min later. Indomethacin restored the expression of Oat1/3, PAH net secretion, and PGE2 clearance. Additionally, indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and nitric oxide production. Notably, indomethacin did not affect inflammation parameters in the kidneys (e.g., monocyte chemoattractant protein-1, ED1+ cells). On the other hand, probenecid blocked the indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular indomethacin uptake abrogates the beneficial effect of indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.