Naik Sindhu, Wood Andrew R, Ongenaert Maté, Saidiyan Paniz, Elstak Edo D, Lanz Henriëtte L, Stallen Jan, Janssen Richard, Smythe Elizabeth, Erdmann Kai S
Department of Biomedical Science, Centre of Membrane Interactions and Dynamics, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
Int J Mol Sci. 2021 May 19;22(10):5361. doi: 10.3390/ijms22105361.
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.
洛氏综合征和丹特II型疾病是X连锁单基因疾病，其特征为近端肾小管的肾重吸收缺陷，由编码肌醇-5-磷酸酶的OCRL基因突变引起。由于慢性肾病及相关并发症的发展，洛氏综合征患者的预期寿命大幅缩短。需要有针对洛氏综合征/丹特II型疾病的生理性人体体外模型，以研究潜在的疾病机制，并识别和表征潜在药物及药物靶点。在此，我们描述了一种芯片上近端肾小管器官模型，该模型将三维肾小管结构与流体流动剪切应力相结合，模拟了洛氏综合征/丹特II型疾病的特征。我们证明了我们的体外模型在药物靶点验证方面具有高度适用性。此外，利用该模型，我们证明缺乏OCRL表达的近端肾小管细胞会上调上皮-间质转化（EMT）的典型标志物，包括转录因子SNAI2/蛞蝓蛋白，并显示胶原蛋白表达和沉积增加，这可能导致如在洛氏综合征和丹特II型疾病中观察到的间质纤维化和疾病进展。
