A 3D renal proximal tubule on chip model phenocopies Lowe syndrome and Dent II disease tubulopathy.

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 underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here we describe a proximal tubule organ on chip model combining 3D tubule architecture with fluid flow shear stress, which phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the principal 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. Differential gene expression analysis between OCRL KO_HK2 cells (2 cell lines) vs WT HK2 cells cultured in 3D tubule architecture with fluid flow applying shear stress.