Generation of a Glomerular Filtration Barrier on a Glomerulus-on-a-Chip Platform.
Generation of a Glomerular Filtration Barrier on a Glomerulus-on-a-Chip Platform.
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DOI：
10.1007/978-1-0716-1693-2_8
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发表时间：
2021-09
影响因子：
--
通讯作者：
L. Perin;Stefano Da Sacco
中科院分区：
文献类型：
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作者：
L. Perin;Stefano Da Sacco
尽管投入了大量的临床和财政资源，慢性肾脏病（CKD）仍然是全球健康威胁。缺乏可靠的体外系统，可以有效地模拟肾脏和肾小球环境，阻碍了我们的能力，成功地开发新的和更多的肾脏特异性药物。尽管已经描述了在体外产生小管类似物和肾类器官方面的一些成功，但是对于肾的过滤单元（肾小球）的体外组装仍然存在主要挑战。我们最近开发了一种新型的肾小球芯片系统，该系统模拟肾小球滤过屏障的特征和功能，包括其对损伤的反应。该系统概括了体内肾小球的功能和结构，包括渗透选择性;事实上，我们已经证实了胰岛素的自由扩散以及对生理浓度白蛋白的不渗透性。暴露于嘌呤霉素等肾毒性药物可导致白蛋白渗漏显著增加。当暴露于来自具有抗足细胞自身抗体的患者的血清时，芯片显示出与体内临床数据成比例的程度的白蛋白渗漏，在来自任一健康对照的血清中未观察到这种现象，证实了对损伤的功能性应答。我们在这里描述的详细程序，以获得一个芯片上的肾小球系统，复制表型和功能的体内肾小球微环境。
Despite an enormous investment of clinical and financial resources, chronic kidney disease (CKD) remains a global health threat. The lack of reliable in vitro systems that can efficiently mimic the renal and glomerular environment has hampered our ability to successfully develop novel and more renal specific drugs. Even though some success in generating in vitro tubule analogues and kidney organoids has been described, a major challenge remains for the in vitro assembly of the filtration unit of the kidney, the glomerulus. We have recently developed a novel glomerulus-on-a-chip system that mimics the characteristic and functionality of the glomerular filtration barrier, including its response to injury. This system recapitulates the functions and structure of the in vivo glomerulus, including permselectivity; indeed, we have confirmed free diffusion of insulin as well as impermeability to physiological concentrations of albumin. Exposure to nephrotoxic agents like puromycin aminonucleoside leads to a significant increase in albumin leakage. When exposed to sera from patients with anti-podocyte autoantibodies, the chip shows albumin leakage to an extent proportional to in vivo clinical data, phenomenon not observed with sera from either healthy controls, confirming functional response to injury. We describe here the detailed procedure to obtain a glomerulus-on-a-chip system that replicates both phenotypically and functionally the in vivo glomerular microenvironment.