Naik, S., Wood, A.R., Ongenaert, M. et al. (7 more authors) (2021) A 3d renal proximal tubule on chip model phenocopies Lowe syndrome and Dent II disease tubulopathy. International Journal of Molecular Sciences, 22 (10). 5361. ISSN 1661-6596
Abstract
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 dis-ease. We demonstrate the high suitability of our in vitro model for drug target validation. Further-more, 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | organ-on-a-chip; disease modeling; proximal tubule-on-a-chip; Lowe syndrome; fibrosis; microfluidic; OCRL |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Funding Information: | Funder Grant number European Commission - HORIZON 2020 674983 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 10 Jun 2021 13:58 |
Last Modified: | 10 Jun 2021 13:58 |
Status: | Published |
Publisher: | MDPI AG |
Refereed: | Yes |
Identification Number: | 10.3390/ijms22105361 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174740 |