Human induced pluripotent stem cells-derived kidney organoids as in vitro model for diabetic nephropathy and correlation with human kidney pathology

Abstract

Diabetic nephropathy is a leading cause of end stage renal disease worldwide, and mechanisms underlying kidney injury during diabetes mellitus are multiple and not fully understood. In vitro and in vivo available experimental models of diabetic nephropathy fail to recapitulate the complex natural history observed in humans. The development of induced-pluripotent stem cells (iPSCs)-derived renal organoids has provided a new platform to study glucose-induced morphological and metabolic alterations in a 3-dimensional cellular culture that recapitulates the architecture of immature developing human kidneys. We cultured mature iPSCs-derived kidney organoids in standard or high glucose conditions and studied morphological differences using both immunofluorescence, to assess differentiation of renal cell progenitors, and transmission electron microscopy to evaluate ultrastructural hyperglycemia-induced tubular and glomerular changes. Based on the preliminary observations on this novel model of diabetic nephropathy, we addressed podocyte injury in a retrospective cohort of human kidney biopsies, using a quantitative method to measure foot process effacement through electron microscopy imaging. Results were correlated with clinical data collected at the time of the biopsy, to assess the contribution of podocyte injury to the development of proteinuria, in cases of diffuse and nodular diabetic nephropathy.