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Article

A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy

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Department of Biomedical Science, Centre of Membrane Interactions and Dynamics, University of Sheffield, Western Bank, Sheffield S10 2TN, UK
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Galapagos BV, Zernikedreef 16, 2333 CL Leiden, The Netherlands
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Galapagos NV, Generaal de Wittelaan L11, A3, 2800 Mechelen, Belgium
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Mimetas BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands
*
Authors to whom correspondence should be addressed.
Academic Editors: Alexander Tonevitsky, Kati Juuti-Uusitalo and Keijo Viiri
Int. J. Mol. Sci. 2021, 22(10), 5361; https://doi.org/10.3390/ijms22105361
Received: 28 April 2021 / Revised: 14 May 2021 / Accepted: 18 May 2021 / Published: 19 May 2021
(This article belongs to the Special Issue Novel Biorelevant Intestinal Epithelial In Vitro Models)
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. View Full-Text
Keywords: organ-on-a-chip; disease modeling; proximal tubule-on-a-chip; Lowe syndrome; fibrosis; microfluidic; OCRL organ-on-a-chip; disease modeling; proximal tubule-on-a-chip; Lowe syndrome; fibrosis; microfluidic; OCRL
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MDPI and ACS Style

Naik, S.; Wood, A.R.; Ongenaert, M.; Saidiyan, P.; Elstak, E.D.; Lanz, H.L.; Stallen, J.; Janssen, R.; Smythe, E.; Erdmann, K.S. A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy. Int. J. Mol. Sci. 2021, 22, 5361. https://doi.org/10.3390/ijms22105361

AMA Style

Naik S, Wood AR, Ongenaert M, Saidiyan P, Elstak ED, Lanz HL, Stallen J, Janssen R, Smythe E, Erdmann KS. A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy. International Journal of Molecular Sciences. 2021; 22(10):5361. https://doi.org/10.3390/ijms22105361

Chicago/Turabian Style

Naik, Sindhu, Andrew R. Wood, Maté Ongenaert, Paniz Saidiyan, Edo D. Elstak, Henriëtte L. Lanz, Jan Stallen, Richard Janssen, Elizabeth Smythe, and Kai S. Erdmann. 2021. "A 3D Renal Proximal Tubule on Chip Model Phenocopies Lowe Syndrome and Dent II Disease Tubulopathy" International Journal of Molecular Sciences 22, no. 10: 5361. https://doi.org/10.3390/ijms22105361

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