A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy.
A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy.
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DOI：
10.3390/ijms22105361
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发表时间：
2021-05-19
影响因子：
5.6
通讯作者：
Erdmann KS
中科院分区：
文献类型：
--
作者：
Naik S;Wood AR;Ongenaert M;Saidiyan P;Elstak ED;Lanz HL;Stallen J;Janssen R;Smythe E;Erdmann KS
Lowe综合征和Dent II病是X连锁单基因疾病，其特征是近端小管中的肾重吸收缺陷，由编码肌醇-5-磷酸酶的OCRL基因突变引起。由于慢性肾脏疾病和相关并发症的发展，患有Lowe综合征的患者的预期寿命大大缩短。需要用于Lowe综合征/Dent II病的生理人类体外模型来研究基础疾病机制并鉴定和鉴定潜在的药物和药物靶点。在这里，我们描述了一个近端小管器官芯片模型相结合的3D小管结构与流体流动剪切应力，表型模仿劳氏综合征/Dent II病的标志。我们证明了我们的体外模型对药物靶点验证的高度适用性。此外，使用该模型，我们证明了缺乏OCRL表达的近端小管细胞上调上皮-间质转化（EMT）的典型标志物，包括转录因子SNAI 2/Slug，并显示出胶原蛋白表达和沉积增加，这可能有助于间质纤维化和疾病进展，如在Lowe综合征和Dent II病中观察到的。
Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial–mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease.
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