Kidney organoids for nephrotic syndrome modeling
Radboud University Medical Center, Nijmegen, Netherlands
Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolving NS pathogenesis. In previous studies, the detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modelling, as shown by activated slit diaphragm signalling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids could be the preferred model of choice to study idiopathic and congenital podocytopathies.
Human pluripotent stem cell-derived kidney organoids for personalized congenital and idiopathic nephrotic syndrome modeling
Jitske Jansen, Bart Smeets
Added on: 12-14-2022