A 3d renal proximal tubule on chip model phenocopies Lowe syndrome and Dent II disease tubulopathy
| Autor: | Maté Ongenaert, Elizabeth Smythe, Richard A.J. Janssen, Henriëtte L. Lanz, Andrew R. Wood, Jan Stallen, Edo D. Elstak, Kai S. Erdmann, Sindhu Naik, Paniz Saidiyan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
QH301-705.5
microfluidic Disease Nephrolithiasis Models Biological Article Catalysis Kidney Tubules Proximal Inorganic Chemistry 03 medical and health sciences 0302 clinical medicine Tubulopathy Fibrosis Lab-On-A-Chip Devices disease modeling medicine Humans Biology (General) Physical and Theoretical Chemistry QD1-999 Molecular Biology Spectroscopy 030304 developmental biology Phenocopy 0303 health sciences organ-on-a-chip OCRL business.industry Organic Chemistry fibrosis Renal Reabsorption Genetic Diseases X-Linked General Medicine medicine.disease Phosphoric Monoester Hydrolases 3. Good health Computer Science Applications Chemistry Lowe syndrome Oculocerebrorenal Syndrome Phenotype Tubule Mutation Cancer research proximal tubule-on-a-chip business 030217 neurology & neurosurgery Kidney disease |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 10 International Journal of Molecular Sciences, Vol 22, Iss 5361, p 5361 (2021) |
| ISSN: | 1661-6596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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