Discovery of kidney disease targets using multimodal human podocyte injury models.

Podocyte injury is a hallmark of chronic kidney disease (CKD) and organ failure, but whether different injury signals perturb unified or distinct molecular targets remains unclear. Using human induced pluripotent stem cell (hiPSC)-derived podocytes, we modeled cellular injury via exposure to diabetic, inflammatory, chemical toxin, biomechanical, and infectious stressors. Transcriptomic analysis revealed both shared and unique changes in gene expression across injury modes. While drug-induced injuries triggered broader transcriptional responses, conserved pathways related to lysosome function, RNA metabolism, and immune activation were identified across models. Importantly, we discovered NEU1, CD82, ABI3BP, and ADAM17 as targets of human podocyte injury. Analysis of multiple kidney disease patient biopsies confirmed enrichment of these targets, underscoring their in vivo relevance and potential as therapeutic targets. These findings highlight the predictive power of human-relevant experimental models and provide insight into podocyte injury responses, offering a framework for future precision medicine approaches.