Abstract: Acute kidney injury (AKI) and chronic kidney disease (CKD) are major clinical challenges with limited treatment options. Human induced pluripotent stem cell-derived nephron progenitor cells (hiPSC-NPCs) exert renoprotective effects in both AKI and CKD models. In this study, we investigated the mechanisms underlying these therapeutic effects, focusing on vascular endothelial growth factor A (VEGF-A). RNA-seq analysis revealed that VEGF-A, a key angiogenic factor known to protect renal function, is highly expressed in hiPSC-NPCs. Sustained VEGF-A delivery via a bioabsorbable hydrogel scaffold improved renal function in AKI mice by promoting angiogenesis. Conversely, VEGF-A knockout (KO) hiPSC-NPCs exhibited diminished therapeutic effects, leading to increased tubular apoptosis, peritubular capillary rarefaction, and fibrosis in both AKI and CKD models. Furthermore, mass spectrometry identified additional angiogenic factors in hiPSC-NPC-conditioned medium, suggesting that VEGF-A and other secreted factors play key roles in the therapeutic effects of hiPSC-NPCs in both AKI and CKD.
