{"paper_id":"2c771e2c-1056-46fe-9d95-0dc3ee6838d1","body_text":"ABSTRACT\nDiabetic kidney disease involves hyperglycemia, inflammation, and epithelial cell dysfunction, but the relationship between these factors is not well understood. We demonstrate that human kidney organoids treated with elevated glucose exhibit a phenotype of epithelial detachment driven by tissue-intrinsic upregulation of proinflammatory cytokines, which can be targeted therapeutically. High glucose induces morphological deterioration of organoids featuring podocyte and tubular cell detachment without cytotoxicity. Cytokine addition sensitizes organoids to intermediate concentrations of elevated glucose. Transcriptomic analysis reveals that high glucose levels affect cytokine, inflammation, signaling, and cell adhesion pathways, resembling changes in human diabetic kidneys. Inhibitors of cytokines and signaling pathways rescue the high glucose phenotype, which is independent of osmotic effects. Thus, elevated glucose triggers a tissue-intrinsic inflammatory cascade to produce an organ-specific phenotype in epithelial cells. This paradigm is relevant for understanding and potentially treating diabetic complications in the kidneys and possibly other organs.\nCompeting Interest Statement\nNovo Nordisk markets and develops drugs for diabetic disease, including DKD, and holds patents related to their use. AK, HHW, and VD hold shareholder interest in Novo Nordisk. BSF is an inventor on patents and/or patent applications related to human kidney organoid differentiation and disease modeling (these include Three-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human microphysiology, toxicology, and morphogenesis [Japan, US, and Australia], licensed to STEMCELL Technologies; High-throughput automation of organoids for identifying therapeutic strategies [PTC patent application pending]; Systems and methods for characterizing pathophysiology [PTC patent application pending]. BSF holds ownership interest in Plurexa LLC.","source_license":"CC-BY-4.0","license_restricted":false}