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Effect of fluid shear stress on the internalization of kidney-targeted delivery systems in renal tubular epithelial cells.
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2019-11-22 , DOI: 10.1016/j.apsb.2019.11.012 Yingying Xu 1 , Shuo Qin 1 , Yining Niu 1 , Tao Gong 1 , Zhirong Zhang 1 , Yao Fu 1
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2019-11-22 , DOI: 10.1016/j.apsb.2019.11.012 Yingying Xu 1 , Shuo Qin 1 , Yining Niu 1 , Tao Gong 1 , Zhirong Zhang 1 , Yao Fu 1
Affiliation
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Renal tubular epithelial cells (RTECs) are important target cells for the development of kidney-targeted drug delivery systems. Under physiological conditions, RTECs are under constant fluid shear stress (FSS) from original urine in the renal tubule and respond to changes of FSS by altering their morphology and receptor expression patterns, which may affect reabsorption and cellular uptake. Using a microfluidic system, controlled shear stress was applied to proximal tubule epithelial cell line HK-2. Next, 2-glucosamine, bovine serum albumin, and albumin nanoparticles were selected as representative carriers to perform cell uptake studies in HK-2 cells using the microfluidic platform system with controlled FSS. FSS is proven to impact the morphology of HK-2 cells and upregulate the levels of megalin and clathrin, which then led to enhanced cellular uptake efficiencies of energy-driven carrier systems such as macromolecular and albumin nanoparticles in HK-2 cells. To further investigate the effects of FSS on endocytic behavior mediated by related receptors, a mice model of acute kidney injury with reduced fluid shear stress was established. Consistent with in vitro findings, in vivo studies have also shown reduced fluid shear stress down-regulated the levels of megalin receptors, thereby reducing the renal distribution of albumin nanoparticles.
中文翻译：
流体剪切应力对肾小管上皮细胞中肾脏靶向递送系统内在化的影响。
肾小管上皮细胞（RTECs）是开发针对肾脏的药物递送系统的重要靶细胞。在生理条件下，RTEC处于来自肾小管原始尿液的恒定流体剪切应力（FSS）下，并通过改变其形态和受体表达模式来响应FSS的变化，这可能会影响重吸收和细胞摄取。使用微流体系统，将受控的剪应力施加至近端小管上皮细胞系HK-2。接下来，选择2-氨基葡萄糖，牛血清白蛋白和白蛋白纳米颗粒作为代表性载体，使用具有受控FSS的微流体平台系统在HK-2细胞中进行细胞摄取研究。事实证明，FSS会影响HK-2细胞的形态并上调megalin和网格蛋白的水平，进而提高了能量驱动的载体系统（例如HK-2细胞中的大分子和白蛋白纳米颗粒）的细胞吸收效率。为了进一步研究FSS对相关受体介导的内吞行为的影响，建立了具有降低的液体切应力的急性肾损伤小鼠模型。与体外研究结果一致，体内研究还显示出降低的流体剪切应力下调了巨蛋白受体的水平，从而减少了白蛋白纳米颗粒在肾脏的分布。
更新日期：2020-04-20
中文翻译：
流体剪切应力对肾小管上皮细胞中肾脏靶向递送系统内在化的影响。
肾小管上皮细胞（RTECs）是开发针对肾脏的药物递送系统的重要靶细胞。在生理条件下，RTEC处于来自肾小管原始尿液的恒定流体剪切应力（FSS）下，并通过改变其形态和受体表达模式来响应FSS的变化，这可能会影响重吸收和细胞摄取。使用微流体系统，将受控的剪应力施加至近端小管上皮细胞系HK-2。接下来，选择2-氨基葡萄糖，牛血清白蛋白和白蛋白纳米颗粒作为代表性载体，使用具有受控FSS的微流体平台系统在HK-2细胞中进行细胞摄取研究。事实证明，FSS会影响HK-2细胞的形态并上调megalin和网格蛋白的水平，进而提高了能量驱动的载体系统（例如HK-2细胞中的大分子和白蛋白纳米颗粒）的细胞吸收效率。为了进一步研究FSS对相关受体介导的内吞行为的影响，建立了具有降低的液体切应力的急性肾损伤小鼠模型。与体外研究结果一致，体内研究还显示出降低的流体剪切应力下调了巨蛋白受体的水平，从而减少了白蛋白纳米颗粒在肾脏的分布。
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