Podocyte injury damages podocytes in chimeric organoids

Abstract We have previously shown that injury to a subset of podocytes can trigger secondary damage in neighboring podocytes, but whether this phenomenon depends on direct intercellular interaction is unknown. To address this, kidney organoids were generated from nephron progenitor cells of two mouse lines: one expressing a receptor for a podocyte-specific immunotoxin and another expressing a tagged ribosomal protein. In chimeric organoids containing a mosaic of these podocyte types, immunotoxin exposure selectively injured the targeted podocytes and also induced secondary injury in adjacent, non-targeted podocytes. This was evidenced by reduced podocin staining and decreased expression of podocyte-specific genes in the non-targeted podocytes. The bystander effect was absent when organoids of each type were cultured separately but in close proximity, indicating that direct cell-to-cell contact within the same glomerular structure is required. These findings show that podocyte injury can propagate locally within kidney organoids, independent of glomerular filtration or other glomerular cell types, and suggest that local podocyte interactions may contribute to the progression of chronic kidney disease.